1. Field of the Invention
The present invention relates to novel heteroaryl compounds that function as enzyme inhibitors, and particularly to a new class of non-peptidic inhibitors of proteolytic enzymes such as urokinase (uPa).
2. Related Art
Proteases are enzymes that cleave proteins at single, specific peptide bonds. Proteases can be classified into four generic classes: serine, thiol or cysteinyl, acid or aspartyl, and metalloproteases (Cuypers et al., J. Biol. Chem. 257:7086 (1982)). Proteases are essential to a variety of biological activities, such as digestion, formation and dissolution of blood clots, reproduction and the immune reaction to foreign cells and organisms. Aberrant proteolysis is associated with a number of disease states in man and other mammals. The human neutrophil proteases, elastase and cathepsin G, have been implicated as contributing to disease states marked by tissue destruction. These disease states include emphysema, rheumatoid arthritis, corneal ulcers and glomerular nephritis. (Barret, in Enzyme Inhibitors as Drugs, Sandler, ed., University Park Press, Baltimore, (1980)). Additional proteases such as plasmin, C-1 esterase, C-3 convertase, urokinase and tissue-type plasminogen activators, acrosin, and kallikreins play key roles in normal biological functions of mammals. In many instances, it is beneficial to disrupt the function of one or more proteolytic enzymes in the course of therapeutically treating a mammal.
Serine proteases include such enzymes as elastase (human leukocyte), cathepsin G, plasmin, C-1 esterase, C-3 convertase, urokinase and tissue-type plasminogen activators, acrosin, chymotrypsin, trypsin, thrombin, factor Xa and kallikreins.
Human leukocyte elastase is released by polymorphonuclear leukocytes at sites of inflammation and thus is a contributing cause for a number of disease states. Cathepsin G is another human neutrophil serine protease. Compounds with the ability to inhibit the activity of these enzymes are expected to have an anti-inflammatory effect useful in the treatment of gout, rheumatoid arthritis and other inflammatory diseases, and in the treatment of emphysema. Chymotrypsin and trypsin are digestive enzymes. Inhibitors of these enzymes are useful in treating pancreatitis. Inhibitors of urokinase plasminogen activator are useful in treating excessive cell growth disease states, such as benign prostatic hypertrophy, prostatic carcinoma and psoriasis.
Urokinase (urinary-type plasminogen activator or uPA; International Union of Biochemistry Classification Number: EC3.4.21.31) is a proteolytic enzyme which is highly specific for a single peptide bond in plasminogen. It is a multidomain serine protease, having a catalytic xe2x80x9cBxe2x80x9d chain (amino acids (aa) 144-411), and an amino-terminal fragment (xe2x80x9cATFxe2x80x9d, aa 1-143) consisting of a growth factor-like domain (4-43) and a Kringle domain (aa 47-135). The uPA Kringle domain appears to bind heparin, but not fibrin, lysine, or aminohexanoic acid. The growth factor-like domain bears some similarity to the structure of epidermal growth factor (EGF) and is thus also referred to as xe2x80x9cEGF-likexe2x80x9d domain. The single chain pro-uPA is activated by plasmin, cleaving the chain into a two-chain active form that is stabilized by a disulfide bond.
Cleavage of the peptide bond in plasminogen by urokinase (xe2x80x9cplasminogen activationxe2x80x9d) results in the formation of a potent general protease, plasmin. Many cell types use urokinase as a key initiator of plasmin-mediated proteolytic degradation or modification of extracellular support structures (e.g., the extracellular matrix (ECM) and the basement membrane (BM)). Cells exist, move, and interact with each other in tissues and organs within the physical framework provided by the ECM and BM. Movement of cells within the ECM or across the BM requires local proteolytic degradation or modification of these structures, allowing cells to xe2x80x9cinvadexe2x80x9d into adjacent areas that were previously unavailable.
Central to the ability of urokinase to mediate cellular migration and invasiveness is the existence of specific high affinity urokinase receptors (uPARs) which concentrate urokinase on the cell surface, leading to the generation of locally high plasmin concentrations between cells and ECM or BM (Blasi, F., et al., Cell Biol. 104:801-804 (1987); Roldan, A. L., et al., EMBO J. 9:467-74 (1990)). The binding interaction is apparently mediated by the EGF-like domain (Rabbani, S. A., et al., J. Biol. Chem. 267:14151-56 (1992)). Cleavage of pro-uPA into active uPA is accelerated when pro-uPA and plasminogen are receptor-bound. Thus, plasmin activates pro-uPA, which in turn activates more plasmin by cleaving plasminogen. This positive feedback cycle is apparently limited to the receptor-based proteolysis on the cell surface, since a large excess of protease inhibitors is found in plasma, including xcex12 antiplasmin, PAI-1 and PAI-2. High plasmin concentrations between invasive cells and ECM or BM are necessary in order to overcome inhibitory effect of these ubiquitous plasmin inhibitors. Thus, it is cell surface receptor-bound urokinase, and not simply free urokinase secreted by cells, which plays the predominant role in initiating cellular invasiveness.
Plasmin can activate or degrade extracellular proteins such as fibrinogen, fibronectin, and zymogens, including matrix metalloproteinases. Plasminogen activators thus can regulate extracellular proteolysis, fibrin clot lysis, tissue remodeling, developmental cell and smooth muscle cell migration, inflammation, and metastasis. Cellular invasiveness initiated by urokinase is central to a wide variety of normal and disease-state physiological processes (reviewed in Blasi, F., et al., J. Cell Biol. 104:801-804 (1987); Dan, K., et al., Adv. Cancer Res.44:139-266 (1985); Littlefield, B. A., Ann. N.Y. Acad. Sci. 622:167-175 (1991); Saksela, O., Biochim. Biophys. Acta 823:35-65 (1985); Testa, J. E., and Quigley, J. P., Cancer Metast. Rev. 9:353-367 (1990)). Such processes include, but are not limited to, angiogenesis (neovascularization), bone restructuring, embryo implantation in the uterus, infiltration of immune cells into inflammatory sites, ovulation, spermatogenesis, tissue remodeling during wound repair, restenosis and organ differentiation, fibrosis, local invasion of tumors into adjacent areas, metastatic spread of tumor cells from primary to secondary sites, and tissue destruction in arthritis. Inhibitors of urokinase therefore have mechanism-based anti-angiogenic, anti-arthritic, anti-inflammatory, anti-restenotic, anti-invasive, anti-metastatic, anti-osteoporotic, anti-retinopathic (for angiogenesis-dependent retinopathies), contraceptive, and tumoristatic activities. Inhibitors of urokinase are useful agents in the treatment of a variety of disease states, including but not limited to, benign prostatic hypertrophy, prostatic carcinoma and psoriasis.
Beneficial effects of urokinase inhibitors have been reported using anti-urokinase monoclonal antibodies and certain other known urokinase inhibitors. For instance, anti-urokinase monoclonal antibodies have been reported to block tumor cell invasiveness in vitro (Hollas, W., et al., Cancer Res. 51:3690-3695, (1991); Meissauer, A., et al., Exp. Cell Res. 192:453-459 (1991)), tumor metastasis and invasion in vivo (Ossowski, L., J. Cell Biol. 107:2437-2445 (1988); Ossowski, L., et al., J. Cancer Res. 51:274-81 (199 1)), and angiogenesis in vivo (Jerdan, J. A., et al., J. Cell Biol. 115[3 Pt 2]:402a (1991)). In addition, amiloride, a known urokinase inhibitor of only moderate potency, has been reported to inhibit tumor metastasis in vivo (Kellen, J. A., et al., Anticancer Res. 8:1373-1376 (1988)) and angiogenesis/capillary network information in vitro (Alliegro, M. A., et al., J. Cell Biol. 115[3 Pt 2]:402a (1991)).
Urokinase plays a significant role in vascular wound healing and arterial neointima formation after injury, most likely affecting cellular migration. Urokinase mediates plasmin proteolysis, which in turn promotes vascular wound-healing and associated neointima formation (Carmeliet et al., Circ. Res. 81:829-839 (Nov. 1997), Lupu et al., Fibrinolysis 10 Supp 2:33-35 (1996)). A viral serine proteinase inhibitor, SERP-1, has been employed to reduce plaque formation after primary balloon angioplasty in rabbits. This activity has been attributed to the inhibition by SERP-1 of cellular proteinases, such as plasmin or urokinase (Lucas et al., Circulation 94:2890-2900 (1996)).
A need continues for non-peptidic compounds that are potent and selective urokinase inhibitors, and which possess greater bioavailability and fewer side-effects than currently available urokinase inhibitors. Accordingly, new classes of potent urokinase inhibitors, characterized by potent inhibitory capacity and low toxicity, are potentially valuable therapeutic agents for a variety of conditions.
The present invention is broadly directed to the use of heteroaryl amidines, methylamidines and guanidines having Formula I (below) as protease inhibitors, preferably as urokinase inhibitors.
Compounds of the present invention exhibit anti-urokinase activity via direct, selective inhibition of urokinase, or are intermediates useful for forming compounds having such activity. Compounds of the present invention inhibit urokinase and are, therefore, useful anti-angiogenic, anti-arthritic, anti-inflammatory, anti-restenotic, anti-invasive, anti-metastatic, anti-osteoporotic, anti-retinopathic (for angiogenesis-dependent retinopathies), contraceptive, and tumoristatic treatment agents. For example, such treatment agents are useful in the treatment of a variety of disease states, including but not limited to, benign prostatic hypertrophy, prostatic carcinoma, tumor metastasis and psoriasis.
Also provided are methods to inhibit extracellular proteolysis, methods to treat benign prostatic hypertrophy, prostatic carcinoma, tumor metastasis, psoriasis, and other conditions by administering the compound of Formula I.
A number of the heteroaryl compounds described herein are novel compounds. Therefore, the present invention is also directed to novel compounds of Formula I.
Further provided are pharmaceutical compositions comprising a compound of Formula I and one or more pharmaceutically acceptable carriers or diluents and said pharmaceutical compositions further comprising a thrombolytic agent such as tissue plasminogen activator and streptokinase.
Further provided are methods of synthesizing compounds of Formula I.
The present invention is broadly directed to a method of inhibiting proteases, particularly serine proteases, by contacting a serine protease with a compound of the general Formula I: 
or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein:
X is O, S or NR7, where R7 is hydrogen, alkyl, aralkyl, hydroxy(C2-4)alkyl, or alkoxy(C2-4)alkyl;
Y is a direct covalent bond, CH2 or NH;
Z is NR5R6, hydrogen or alkyl, provided that Y is NH whenever Z is hydrogen or alkyl;
R1 is hydrogen, amino, hydroxy, halogen, cyano, C1-4alkyl or xe2x80x94CH2R, where R is hydroxy, amino or C1-3alkoxy;
R2 and R3 are independently:
i. hydrogen;
ii. halogen;
iii. hydroxy;
iv. nitro;
v. cyano;
vi. amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino, monoheterocycleamino, diheterocycleamino, monoalkylmonoheterocycleamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, aralkylsulfonylamino, aralkenylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, di(aralkylsulfonyl)amino, di(aralkenylsulfonyl)anmino, di(arylsulfonyl)amino, or di-(heteroarylsulfonyl)amino, formylamino, alkanoylanmino, alkenoylamino, alkynoylamino, aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino, heteroaralkanoylamino, H(S)CNHxe2x80x94, or thioacylamino, wherein any of the aryl or heteroaryl containing groups can be optionally substituted on the aromatic ring and wherein any of the heterocycle containing groups can be optionally ring substituted;
vii. aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl, aminoacyl, monoarylaminocarbonyl, diarylaminocarbonyl or monoalkylmonoarylaminocarbonyl;
viii. aminothiocarbonyl, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, thioacyl or aminothioacyl;
ix. aminocarbonylamino, mono- and dialkylaminocarbonylamino, mono- and diarylaminocarbonylamino, or mono- and diaralkylaminocarbonylamino;
x. aminocarbonyloxy, mono- and dialkylaminocarbonyloxy, mono- and diarylaminocarbonyloxy, mono- and diaralkylaminocarbonyloxy;
xi. aminosulfonyl, mono- and dialkylaminosulfonyl, mono- and diarylaminosulfonyl, or mono- and diaralkylaminosulfonyl;
xii. alkoxy, or alkylthio, wherein the alkyl portion of each group may be optionally substituted,
xiii. aralkoxy, aryloxy, heteroaryloxy, aralkylthio, arylthio, or heteroarylthio, wherein the aryl portion of each group can be optionally substituted;
xiv. alkylsulfonyl, wherein the alkyl portion can be optionally substituted;
xv. aralkylsulfonyl, aralkenylsulfonyl, arylsulfonyl or heteroarylsulfonyl, wherein the aryl portion of each group can be optionally substituted;
xvi. alkenyl, or alkynyl;
xvii. optionally substituted aryl;
xviii. optionally substituted alkyl;
xix. optionally substituted aralkyl;
xx. optionally substituted heterocycle; or
xxi. optionally substituted cycloalkyl; and
R4, R5 and R6are independently hydrogen, C1-4alkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl, carboxyalkyl, cyano, amino, alkoxy, or hydroxy, or xe2x80x94CO2Rw, where
Rw is alkyl, cycloalkyl, phenyl, benzyl, 
where Rd and Re are independently hydrogen, C1-6alkyl, C2-6alkenyl or phenyl, Rf is hydrogen, C1-6alkyl, C2-6alkenyl or phenyl, Rg is hydrogen, C1-6alkyl, C2-6alkenyl or phenyl, and Rh is aralkyl or C1-6alkyl.
The present invention is also directed to novel compounds of Formula I, where X, Y and R1-R6 are as defined above; provided that at least one of R2 or R3 is selected from the group consisting of:
(a) an optionally substituted alkyl group, preferably C1-C6alkyl, more preferably C1-C3;
(b) alkoxy, aryloxy, alkylthio or arylthio, any of which is optionally substituted;
(c) optionally substituted C6-C14aryl, or optionally substituted aralkyl, except that R3 is not nitrophenyl or aminophenyl, when R1 and R2 are both hydrogen or methyl;
(d) optionally substituted heterocycle; and
(e) optionally substituted cycloalkyl.
When an alkyl-containing group, heterocyclic-containing group or aryl-containing group of R2 or R3 is optionally substituted, the optional substituents can be 1 to 4 non-hydrogen substituents, provided that the resulting compound is stable. Values of optional substituents on alkyl groups are halogen, hydroxy, thiol, amino, monoalkylamino, dialkylamino, formylamino, aminoiminomethyl, acylamino, aminoacyl, mono- or di-alkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, mono- or diarylaminocarbonyloxy, mono- or diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino, aralkylsulfonyl amino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, mono- or di-alkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, alkylthio and arylthio.
Preferred values of optional substituents on an alkyl group are chloro, hydroxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, formylamino, C2-6acylamino, aminocarbonyl, C2-8aminoacyl, C1-6alkoxy, C6-14aryloxy, carboxy, carboxy(C1-6)alkyl, C2-8alkoxycarbonyl, nitro, cyano, trifluoromethyl, C1-6alkylthio, C6-14arylthio, C1-6alkylsulfonylamino, C7-15aralkylsulfonylamino, C6-10arylsulfonylamino, mono- or di(C1-6)alkylaminocarbonyloxy, mono- or di-(C6-10)arylaminocarbonyloxy, mono- or di(C7-15)aralkylcarbonytoxy, C1-6alkoxycarbonylamino, C7-C15aralkoxycarbonylamino, and C6-C10aryloxycarbonylamino.
Preferred values of optional substituents on aryl-containing and heterocyclic-containing groups include chloro, hydroxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, formylamino, C2-8acylamino, aminocarbonyl, C2-8aminoacyl, C3-7cycloalkyl, C1-6alkyl, C1-6alkoxy, C6-14aryloxy, carboxy, carboxy(C1-6)alkyl, C2-8alkoxycarbonyl, nitro, cyano, trifluoromethyl, C1-6alkylthio, C6-14arylthio, C6-14aryl, substituted phenyl, tetrazolyl, thienyl (further optionally substituted by one, two or three of chloro, hydroxy, C1-4alkyl, C1-4alkoxy, amino or carboxy), 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, C1-6alkylsulfonylamino, C7-15aralkylsulfonylamino, C1-6arylsulfonylamino, C1-6alkyl/sulfonyl, C6-10arylsulfonyl, mono- or di(C1-6)alkylaminocarbonyloxy, mono- or di- C6-10arylaminocarbonyloxy, mono- or di-(C7-15)aralkylcarbonyloxy, C1-6alkoxycarbonylamino, C7-C15aralkoxycarbonylamino, C6-C10aryloxycarbonylamino, C2-6thioacylamino, aminothiocarbonyl, and C2-8aminothioacyl.
Preferred values of R1 include hydrogen, amino, hydroxy and fluoro.
A preferred value of R2 is Formula II: 
where Ar is phenyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl (thiophenyl), pyrrolyl, oxazolinyl and benzothienyl.
Preferred values of R3 include C1-4alkyl (optionally substituted), halogen, amino, acylamino, C1-6alkylthio (such as methylthio or ethylthio), C1-6alkoxy (such as methoxy and ethoxy), trifluoromethyl, methylsulfonyl, and benzylthio.
A preferred value of X is divalent sulfur (S).
Preferred values of Y are a covalent bond or xe2x80x94NHxe2x80x94, most preferably a covalent bond.
Preferred values of R4, R5 and R6 in Formula I are hydrogen, hydroxy, cyano, C1-6 alkyl, or C1-6 alkoxy. Suitable values of R4, R5 and R6 include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, and ethoxy. In the most preferred embodiments, R4, R5 and R6 are each hydrogen.
Preferred values of R4, R5 and R6 in Formula I also include prodrugs such as xe2x80x94CO2Rw, where Rw, in each instance, is preferably one of C1-4alkyl, C4-7cycloalkyl or benzyloxycarbonyl. Suitable values of R4, R5 and R6 include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, ethoxy, cyano, xe2x80x94CO2CH3, xe2x80x94CO2CH2CH3 and xe2x80x94CO2CH2CH2CH3. In the most preferred embodiments, R4, R5 and R6 are each hydrogen.
Also preferred at R4, R5 and R6 is the group xe2x80x94CO2Rw, where Rw is one of 
where Rd-Rh are defined as above. When R4, R5 and R6 are xe2x80x94CO2Rw, where Rw is one of one of these moieties, the resulting compounds are prodrugs that possess desirable formulation and bioavailability characteristics. A preferred value for each of Rd, Rc and Rg is hydrogen, Rf is methyl, and preferred values for Rh include benzyl and tert-butyl.
Preferred values of R7 include hydrogen, C1-6alkyl, C6-10ar(C1-4)alkyl, and C2-6hydroxyalkyl. Suitable values are hydrogen, methyl, ethyl, and benzyl.
The term xe2x80x9calkylxe2x80x9d as employed herein by itself or as part of another group refers to both straight and branched chain radicals of up to 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl.
The term xe2x80x9calkenylxe2x80x9d is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Preferably, the alkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length most preferably from 2 to 4 carbon atoms in length.
The term xe2x80x9calkynylxe2x80x9d is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1-propylene, 2-propylene, and the like. Preferably, the alkynyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length, most preferably from 2 to 4 carbon atoms in length.
In all instances herein where there is an alkenyl or alkynyl moiety as a substituent group, the unsaturated linkage, i.e., the vinylene or acetylene linkage is preferably not directly attached to a nitrogen, oxygen or sulfur moiety.
The term xe2x80x9calkylthioxe2x80x9d as employed herein by itself or as part of another group refers to a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is limited thereto, bonded to a sulfur atom, including, but not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, and the like. Preferably the alkylthio chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length.
The term xe2x80x9calkoxyxe2x80x9d as employed herein by itself or as part of another group refers to a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Preferably the alkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length.
The term xe2x80x9ccycloalkylxe2x80x9d as employed herein by itself or as part of another group refers to cycloalkyl groups containing 3 to 9 carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine with chlorine being preferred.
The term xe2x80x9cacylxe2x80x9d as employed herein by itself or as part of another group refers to the group xe2x80x94C(O)Rg where Rg is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl. Preferred acyl groups are alkanoyl, aralkanoyl and aroyl groups (xe2x80x94C(O)Rg where Rg is C1-8alkyl, C6-10aryl(C1-4)alkyl or C6-10aryl).
The term xe2x80x9cthioacylxe2x80x9d as employed herein by itself or as part of another group refers to the group xe2x80x94C(S)Rg where Rg is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl, preferably C1-8alkyl.
The term xe2x80x9cthiocarbonylxe2x80x9d as employed herein by itself or as part of another group refers to the group xe2x80x94C(S)xe2x80x94.
The term xe2x80x9cmonoalkylaminexe2x80x9d as employed herein by itself or as part of another group refers to an amino group which is substituted with one alkyl group having from 1 to 6 carbon atoms.
The term xe2x80x9cdialkylaminexe2x80x9d as employed herein by itself or as part of another group refers to an amino group which is substituted with two alkyl groups, each having from 1 to 6 carbon atoms.
The term xe2x80x9carylxe2x80x9d as employed herein by itself or as part of another group refers to monocyclic- or bicyclic aromatic groups containing from 6 to 14 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.
The term xe2x80x9caralkylxe2x80x9d or xe2x80x9carylalkylxe2x80x9d as employed herein by itself or as part of another group refers to C1-6alkyl groups as discussed above having an aryl substituent, such as benzyl, phenylethyl or 2-naphthylmethyl.
The terms xe2x80x9cheterocyclic,xe2x80x9d xe2x80x9cheterocycloxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d as employed herein by themselves or as part of larger groups refers to a saturated or wholly or partially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Especially useful are rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. Examples of such heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrirnidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
The term xe2x80x9cheteroatomxe2x80x9d is used herein to mean an oxygen atom (xe2x80x9cOxe2x80x9d), a sulfur atom (xe2x80x9cSxe2x80x9d) or a nitrogen atom (xe2x80x9cNxe2x80x9d). It will be recognized that when the heteroatom is nitrogen, it may form an NRyRz moiety, wherein Ry and Rz are, independently from one another, hydrogen or C1 to C8alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7-membered ring.
The term xe2x80x9cheteroarylxe2x80x9d as employed herein refers to groups having 5 to 14 ring atoms; 6, 10 or 14 xcfx80 electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4xcex1H-carbazolyl, carbazolyl, xcex2-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl groups).
The expression xe2x80x9cprodrugxe2x80x9d denotes a derivative of a known direct acting drug, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process. Useful prodrugs are those where R4, R5 and/or R6 are xe2x80x94CO2Rw, where Rw is defined above. See, U.S. Pat. No. 5,466,811 and Saulnier et al., Bioorg. Med. Chem. Lett. 4:1985-1990 (1994).
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that one or more hydrogens of the designated moiety are replaced with a selection from the indicated group, provided that no atom""s normal valency is exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens attached to an atom of the moiety are replaced.
By xe2x80x9cstable compoundxe2x80x9d or xe2x80x9cstable formulaxe2x80x9d is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.
A first preferred group of compounds falling within the scope of the present invention include compounds of Formula I wherein X is sulfur or oxygen; Y is a covalent bond or xe2x80x94NHxe2x80x94; R1 is hydrogen, amino, hydroxy or halogen; R4, R5 and R6 are independently hydrogen, C1-4alkyl, amino, cyano, C1-4alkoxy or hydroxy, and are preferably all hydrogen; one of R2 or R3 is hydrogen, C1-6alkyl (optionally substituted with hydroxy, amino, carboxy or aminocarbonyl), C1-6alkylthio or C1-6alkoxy; and the other of R2 or R3 is aminoacyl, acylamino, aminosulfonyl, sulfonylamino, aminocarbonylamino, alkoxycarbonylamino, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted benzothienyl, optionally substituted furanyl, optionally substituted pyrazolyl or optionally substituted pyridyl.
Specific compounds within the scope of the invention include the compounds described in the Examples, such as the following:
4-[4-(4-chlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-phenyl-5-methylthiothiophene-2-carboxamidine;
4-[4-(2,4-dichlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-(4-methylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
methyl 4-[4-(4-phenylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxylate;
4-[4-(3-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine,
4-[4-(3-hydroxyphenyl)thiazol-2-yl]-5-methylthiothlophene-2-carboxamidine,
4-(4-phenylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine,
4-[4-(4-nitrophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine,
4-[4-(3,4-ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine,
4-[4-(3,4-propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine,
4-[4-(4-(naphth-2-yl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine,
4-isopropylsulfonyl-5-methylthiothiophene-2-carboxamidine;
4-phenyl-5-methylthiothiophene-2-carboxamidine;
4-[4-(4-chlorophenyl)thiazol-2-yl]-methylthlothiophene-2-carboxamidine;
4-[4-(4-phenylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(4-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-(2-naphthylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
4-[4-(4-chloro-3-methylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-(5-methyl-4-phenylthiazol-2-yl)-5-methylthlothiophene-2-carboxamidine;
4-[4-(4-chloro-3-nitrophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-(5-phenyloxazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
4-[4-(3-fluoro-5-trifluoromethylphenyl)-5-methylthiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3,5-bis(trifluoromethyl)phenyl)-5-methyl-thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3-fluoro-5-trifluoromethylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3-bromophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3,4-methylenedioxyphenyl)thiazol-2-yl]-5-methylthiothlophene-2-carboxamidine;
4-[4-(4-methylphenyl)thiazol-2-yl]-5-methylthlothiophene-2-carboxamidine;
4-[4-(3,5-bis(trifluoromethyl)phenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(2-methoxyphenyl)thiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
4-(4-phenylimidazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-(4-(2,4-dimethoxyphenyl)thiazol-2-yl-5-methyithiothiophene-2-carboxamidine;
4-(4-benzylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
4-[4-(3,4-dichlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3-methylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3,5-dimethoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(2-methylphenyl)thiazol-2-yl]-5-methylthiothlophene-2-carboxamidine;
4-[4-(2,5-dimethoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-(4,5-diphenylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
4-(2-phenyl)thiazol-4-yl-5-methylthiothiophene-2-carboxamidine;
4-[4-(2-chloro-3-pyridyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamdine;
4-[4-(phenoxymethyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-(4-cyclohexylthiazol-2-yl)-5-methylthiothophene-2-carboxamidine;
4-[4-(4-chlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(2-hydroxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3-trifluoromethoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(2-chloro-4-pyridyl)thiazol-2-yl]-5-methylthlothiophene-2-carboxamidine;
4-(5-phenyl-2-pyridyl)-5-methylthiothiophene-2-carboxamidine;
4-[2-(2-chlorophenylamino)thiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(3-methoxyphenylamino)thiazol-4-yl]-5-methylthlothlophene-2-carboxamidine;
4-[2-(phenylamino)thiazol-4-yl]-5-methylthiothlophene-2-carboxamidine;
4-[2-(2,5-dimethoxyphenylamino)thiazol-4-yl]-5-methylthlothiophene-2-carboxamidine;
4-(2-aminothiazol-4-yl)-5-methylthiothiophene-2-carboxamidine;
4-[2-(4-chloro-2-methylphenylamino)thiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(4-dimethylaminophenyl amino)thiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(4-methoxyphenylamino)thiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(4-hydroxy-3-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3-hydroxy-4-methoxyphenyl)thiazol-2-yl]-5-methylthlothiophene-2-carboxamidine;
4-[2-(2-fluorophenylamino)thiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(2,4,5-trimethylphenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(3-chloro-2-methylphenyl)aminothiazol-4-yi]-5-methylthlothiophene-2-carboxamidine;
4-[2-(2-isopropylphenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(4-benzyloxyphenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(2-bromophenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(2,5-dichlorophenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(2-bromo-4-methylphenyl)aminothiazol-4-yl]-5-methylthiothlophene-2-carboxamidine;
4-[2-(2,3-dichlorophenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(3 ,4,5-trimethoxyphenyl)aminothiazol-4-yl ]-5-methylthiothiophene-2-carboxamidine;
4-[2-(2-piperidinylethyl)aminothiazol-4yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(4-methylphenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-(4-phenyloxazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
4-[2-(diphenylmethyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine; and
4-[2-(3-phenylpropyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine,
as well as pharmaceutically acceptable salts thereof, for example the hydrochloride, hydrobromide and acetate salts thereof, or a prodrug thereof.
A second preferred group of compounds falling within the scope of the present invention include compounds of Formula I wherein X is sulfur or oxygen; Y is a covalent bond or xe2x80x94NHxe2x80x94; Z is NR5R6; R1 is hydrogen, amino, hydroxy or halogen; R4, R5 and R6 are independently hydrogen, C1-4alkyl, amino, C1-4alkoxy or hydroxy, and are preferably all hydrogen; one of R2 or R3 is hydrogen, C1-6alkylthio, C1-6alkyl optionally substituted with OH, NH2, COOH or aminocarbonyl, or C1-6alkoxy; and the other of R2 or R3 is: 
where:
Ar is a group selected from the group consisting of phenyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, furanyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl (thiophenyl), tetrazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, oxazolinyl, isoxazolinyl, imidazolinyl, triazolyl, pyrrolinyl, benzothiazolyl, benzothienyl, benzimidazolyl, 1,3-oxazolidin-2-onyl, imidazolin-2-onyl (preferably phenyl, thiazolyl, thiazolinyl, oxazolinyl, isothiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, thienyl, pyrrolyl, oxazolinyl and benzothienyl), any of which can optionally include an exocyclic xe2x95x90O (keto) or xe2x95x90NRv (imino) group, where Rv is alkyl, aryl, aralkyl, alkylamino, arylimino or aralkylimino; and
R8 and R9 are independently selected from the group consisting of hydrogen, halogen, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, arylamino, mono- and di-(C6-14)arylamino, mono- and di-(C6-14)ar(C1-6)alkylamino, formylamino, C2-6acylamino, aminocarbonyl, C2-8aminoacyl, C2-6thioacylamino, aminothiocarbonyl, C2-8 aminothioacyl, C1-6alkyl, C3-8cycloalkyl, C1-6alkoxy, carboxy, carboxy(C1-6)alkyl, C2-8alkoxycarbonyl, nitro, cyano, trifluoromethyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, furanyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl (thiophenyl), tetrazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, oxazolinyl, isoxazolinyl, imidazolinyl, triazolyl, pyrrolinyl, benzothiazolyl, benzothienyl, benzimidazolyl, 1,3-oxazolidin-2-onyl, imidazolin-2-onyl, C6-14aryloxy, C1-6alkylthio, C6-14arylthio, C6-14aryl, or C6-14ar(C1-6)alkyl, wherein the aforementioned heteroaryl groups and the aryl portions of C6-14aryloxy, mono- and di C6-14aryl amino, mono- and di- C6-14ar(C1-6)alkylamino, C6-14arylthio, C6-14ar(C1-6)alkyl, and C6-14aryl can be further optionally substituted, preferably by one, two or three of halogen, hydroxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, formylamino, C1-4acylamino, C1-4aminoacyl, mono- or di-(C1-4)alkylaminocarbonyl, thiocarbonylamino, C1-4thioacylamino, aminothiocarbonyl, C1-4alkoxy, C6-10aryloxy, aminocarbonyloxy, mono- or di(C1-4)alkylaminocarbonyloxy, mono- or di(C6-10)arylaminocarbonyloxy, mono- or di(C7-15)aralkylaminocarbonyloxy, C1-4alkylsulfonyl, C6-10arylsulfonyl, (C7-15)aralkylsulfonyl, C1-4alkylsulfonylamino, C6-10arylsulfonylamino, (C7-15)aralkylsulfonylamino, aminosulfonyl, mono- and di-alkylaminosulfonyl, mono- and di-arylaminosulfonyl, mono- and di-aralkylamninosulfonyl, C1-4alkoxycarbonylamino, C7-15aralkoxycarbonylamino, C6-10aryloxycarbonylamino, mono- or di-(C1-4)alkylaminothiocarbonyl, C7-15aralkoxy, carboxy, carboxy(C1-4)alkyl, C1-4alkoxycarbonyl, C1-4alkoxycarbonylalkyl, carboxy(C1-4)alkoxy, alkoxycarbonylalkoxy, nitro, cyano, trifluoromethyl, C1-4alkylthio and C6-10arylthio, or by 3,4-methylenedioxy, 3,4-ethylenedioxy, and 3,4-propylenedioxy.
Preferred values of R8 and R9 are halogen, C1-6alkyl, C1-4alkoxy, hydroxy, nitro, trifluoromethyl, C6-10aryl (further optionally substituted by one or two of chloro, halogen, C1-6alkyl, C1-6alkoxy, hydroxy, nitro, trifluoromethyl, carboxy, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, or amino), 4-phenylphenyl (biphenyl), C1-6aminoalkyl, carboxy, C1-6alkyl, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, amino, C1-6alkanoylamino, C6-14aroylamino, C1-6hydroxyalkyl, thienyl (further optionally substituted by one or two of chloro, amino, methyl, methoxy, or hydroxy) and tetrazolyl. More preferably, R2 is thienyl, oxazolyl, or thiazolyl, optionally substituted by any of the aforementioned groups.
Examples of preferred R8 and R9 groups include 4-chlorophenyl, 2,4-dichlorophenyl, methyl, 4-nitrophenyl, 3-nitrophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3-(2,4-dimethylthien-5-yl)phenyl, 3-hydroxyphenyl, 5-(carboxymethyl)thien-2-yl, phenyl, 3,4-ethylenedioxyphenyl, 3,4-propylenedioxyphenyl, naphth-2-yl, 3-phenyl-4-(tetrazol-5-yl)phenyl, 2,4-dichlorophenyl), 4-phenylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-phenylphenyl, phenyithiomethyl, 2-chloro-4,5-dimethoxyphenyl, 4-chloro-3-methylphenyl, 5-methyl-4-phenyl, 4-chloro-3-nitrophenyl, 3-fluoro-5-trifluoromethylphenyl, 3,5-bis(trifluoromethyl), 3-fluoro-5-trifluoromethylphenyl, 3-bromophenol, 3,4-methylenedioxyphenyl, 4-methylphenyl, 3-methylphenyl, 3,5-bis(trifluoromethyl)phenyl, 2-methoxyphenyl, 6-phenyl-2-pyridyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, benzyl, 3,4-dichlorophenyl, 3-methylphenyl, 3,5-dimethoxyphenyl, 2-methylphenyl, 2,5-dimethoxyphenyl, 2-chloro-3-pyridyl, phenoxymethyl, cyclohexyl, 2-hydroxyphenyl, 3-trifluoromethoxyphenyl, 2-chloro-4-pyridyl, 3-chloro-4-pyridyl, 2-chlorophenylamino, 3-methoxyphenylamino, phenylamino, 2,5-dimethoxyphenylamino, amino, 4-chloro-2-methylphenylamino, 4-dimethylaminophenylamino, 4-methoxyphenylamino, 4-hydroxy-3-methoxyphenyl, 3-hydroxy-4-methoxyphenyl, 2-fluorophenylamino, 2,4,5-trimethylphenylamino, 3-chloro-2-methylphenylamino, 2-isopropylphenylamino, 4-benzyloxyphenylamino, 2-bromophenylamino, 2,5-dichlorophenylamino, 2-bromo-4-methylphenylamino, 2,3-dichlorophenylamino, 3,4,5-trimethoxyphenylamino, 2-piperidinylethylamino, 4-methylphenylamino, 2-thienyl, 2-5,6,7,8-tetrahydronaphthyl, 3-(2-phenoxyacetic acid)phenyl, 2-(2-phenoxyacetic acid)phenyl, diphenylmethylamino, 3-phenylpropylamino, 3-phenylphenyl, phenylthiomethyl, 2-chloro-4,5-dimethoxyphenyl, and isopropyl.
A third preferred group of compounds are those of Formula I wherein:
X is sulfur;
Y is a covalent bond;
Z is NR5R6;
R1 is hydrogen;
R3 is methylthio or methyl;
R4, R5 and R6 are all hydrogen; and
R2 is Formula II, where Ar is phenyl, thiazolyl, oxazolyl, benzothienyl, pyridyl, or imidazolyl; and R8 and R9 are independently hydrogen, or C6-10aryl or heterocycle, optionally substituted by one, two or three of chloro, hydroxy, C1-4alkyl, C3-6cycloalkyl, C1-4alkoxy, amino, carboxy, phenyl, naphthyl, biphenyl, hydroxyphenyl, methoxyphenyl, dimethoxyphenyl, carboxyalkoxyphenyl, alkoxycarbonylalkoxy, carboxyethoxy, alkylsulfonylaminophenyl, arylsulfonylaminophenyl, acylsulfonylaminophenyl, aralkylsulfonylaminophenyl, heteroarylsulfonylaminophenyl where the heteroaryl portion is optionally halo or C1-6alkyl substituted, chlorophenyl, dichlorophenyl, aminophenyl, carboxyphenyl, nitrophenyl, or by 3,4-methylenedioxy, 3,4-ethylenedioxy, and 3,4-propylenedioxy.
A fourth preferred group of compounds are those of Formula I wherein:
X is sulfur;
Y is a direct covalent bond;
Z is NR5R6;
R1 is hydrogen;
R2 is alkyl, ar(alkyl), alkylsulfonyl, xe2x80x94SO2-alkyl, amido, amidino, or 
where
Ar is an aromatic or heteroaromatic group selected from the group consisting of phenyl, thiazolyl, oxazolyl, imidazolyl and pyridyl;
R8 and R9 are independently selected from the group consisting of hydrogen, carboxy, phenyl, naphthyl, alkyl, pyridyl, oxazolyl, furanyl, cycloalkyl and amino, any of which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkaryl, heteroaryl, phenyl, naphthyl, alkoxy, aryloxy, hydroxy, amino nitro, thiophenyl, benzothiophenyl, fluorenyl, 3,4-ethylenedioxy, 3,4-methylenedioxy, 3,4-propylenedioxy, arylsulfonamido, alkylsulfonamido and aryloxy, each of said 1 to 3 substituents may be further optionally substituted with one or more groups selected from alkoxy, haloalkyl, halogen, alkyl, amino, acetyl, hydroxy, dialkylamino, dialkylamino acyl, monoalkylaminoacyl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-aryl, or aryl;
R3 is xe2x80x94SO2-alkyl, trifluoromethyl, S(O)-alkyl, hydrogen, alkoxy, alkylthio, alkyl, aralkylthio; and
R4, R5, R6 are hydrogen.
Preferred compounds of this embodiment are those where Ar is a thiazolyl, preferably thiazol-2-yl or thiazol-4-yl, and at least one of R8 and R9 is substituted phenyl, most preferably on the 4-position of the thiazol-2-yl group. Also preferred are compounds where R2 is a 4-phenylthiazol-2-yl group wherein said phenyl is further optionally substituted, and R3 is methylthio.
A fifth preferred group of compounds are those of Formula III: 
or a pharmaceutically acceptable salt or prodrug thereof, where
A is methylthio or methyl;
Gxe2x80x2 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, or a covalent bond;
n is an integer from 1-10, preferably from 1-6;
m is an integer from 0-1; and
Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, aryl or aralkyl, or Rxe2x80x2 and Rxe2x80x3 are taken together with the N atom to which they are attached form a 3-8 membered heterocyclic ring, optionally containing an additional O, N, or S atom, and when said 3-8 membered heterocyclic ring contains an additional N atom, said additional N atom is optionally substituted by hydrogen, C1-4alkyl, C6-10aryl, C6-10ar(C1-4)alkyl, acyl, alkoxycarbonyl or benzyloxycarbonyl.
Most preferred compounds of Formula III are those for which Rxe2x80x2 and Rxe2x80x3, taken together with the N atom to which they are attached, form a ring selected from piperazinyl, pyrrolidinyl, piperidinyl or morpholinyl, which are further optionally substituted with 1 to 4 non-hydrogen substituents selected from halogen, hydroxy, amino, monoalkylamino, dialkylamino, formylamino, acylamino, aminoacyl, mono- or di-alkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, mono- or diarylaminocarbonyloxy, mono- or diarakylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino, arakylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, mono- or di-alkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, alkylthio and arylthio, where each of these substituents has the preferred values set forth for Formulae I and II above.
Examples of preferred compounds of Formula III include:
5-methylthio-4-[4-(3-{[N-(2-morpholin-4-ylethyl)carbamoyl]methoxy}phenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidine,
5-methylthio-4-{4-[3-(2-morpholin-4-yl-2-oxoethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine,
5-methylthio-4-{4-[3-(2-oxo-2-piperazinylethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine,
4-[4-(3-{[N-(2-aminoethyl)carbamoyl]methoxy}phenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine,
4-(4-{3-[2-(4-acetylpiperazinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,
4-(4-{3-[2-(4-methylpiperazinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine, the compound described in Example 151,
5-methylthio-4-[4-(3-{2-oxo-2-[4-benzylpiperazinyl]ethoxy phenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidine,
(D,L)-4-(4-{3-[2-(3-aminopyrrolidinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,
5-methylthio-4-(4-[3-(2-oxo-2-piperidylethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine,
(D,L)-ethyl 1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-2-carboxylate,
5-methylthio-4-{4-[3-(2-oxo-2-pyrrolidinylethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine, 5-methylthio-4-[4-(3-{2-oxo-2-[4-benzylpiperidyl]ethoxy}phenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidine,
(D,L)-4-(4-{3-[2-(3-methylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,
4-(4-{3-[2-(4-methylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,
4-(4-{3-[2-(2-azabicyclo[4.4.0]dec-2-yl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,
(D,L)-ethyl 1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-3-carboxylate,
5-methylthio-4-{4-[3-(2-oxo-2-(1,2,3,4-tetrahydroquinolyl)ethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine,
ethyl 1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-4-carboxylate,
4-(4-{3-[2-((3R)-3-hydroxypiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,
D,L-4-(4-{3-[2-(2-ethylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,
4-(4-{3-[2-((3S)-3-hydroxypyrrolidinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,
D,L4-[4-(3-{2-[3-(hydroxymethyl)piperidyl]-2-oxoethoxylphenyl}(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine,
4-{4-[3-(2-{(2R)-2-[(phenylamino)methyl]pyrrolidinyl}-2-oxoethoxy)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidine,
4-[4-(3-{2-[(3R)-3-(methoxymethyl)pyrrolidinyl]-2-oxoethoxy}phenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine,
1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-3-carboxamide, and
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxylacetic acid;
or pharmaceutically acceptable salts or prodrugs thereof.
A sixth preferred group of compounds are those of Formula IV: 
or a pharmaceutically acceptable salt or prodrug thereof, where
A is methylthio or methyl; and
Rxe2x80x2xe2x80x3 is hydrogen, C6-14aryl, C1-6alkyl, C1-6alkoxy (C6-14)aryl, amino(C6-14)aryl, monoalkylamino(C6-14)aryl, dialkylamino(C6-14)aryl, C6-10ar(C1-6)alkyl, heterocycle(C2-6)alkyl such as morpholinoalkyl, piperazinylalkyl and the like, C1-6alk(C6-14)aryl, amino(C1-6)alkyl, mono(C1-6)alkylamino(C1-6)alkyl, di(C1-6)alkylamino(C1-6)alkyl, hydroxy(C6-14)aryl, or hydroxy(C1-6)alkyl, where the aryl and heterocyclic rings can be further optionally substituted by 1-4 non-hydrogen substituents selected from halogen, hydroxy, amino, mono(C1-6)alkylamino, di(C1-6)alkylamino, formylamino, (C1-6)acylamino, amino(C1-6)acyl, mono- or di-(C1-6)alkylaminocarbonyl, thiocarbonylamino, (C1-6)thioacylamino, aminothiocarbonyl, (C1-6)alkoxy, (C6-10)aryloxy, aminocarbonyloxy, mono- or di-(C1-6)alkylaminocarbonyloxy, mono- or di-(C6-10)arylaminocarbonyloxy, mono- or di(C6-10)ar(C1-6)alkylaminocarbonyloxy, (C1-6)alkylsulfonyl, (C6-10)arylsulfonyl, (C6-10)ar(C1-6)alkylsulfonyl, (C1-6)alkylsulfonylamino, C6-10arylsulfonylamino, (C6-10)ar(C1-6)alkylsulfonylamino,(C1-6)alkoxycarbonylamino, (C6-10)ar(C1-6)alkoxycarbonylamino, C6-10aryloxycarbonylamino, mono- or di-(C1-6)alkylaminothiocarbonyl, (C6-10)ar(C1-6)alkoxy, carboxy, (C1-6)carboxyalkyl, C1-6alkoxycarbonyl, (C1-6)alkoxycarbonyl(C1-6)alkyl, nitro, cyano, trifluoromethyl, (C1-6)alkylthio and C6-10arylthio.
Examples of preferred compounds of Formula IV include:
4-{2-[(3-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,
4-{2-[(4-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,
4-(2-{[4-(dimethylamino)phenyl]amino}(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,
4-{2-[(4-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl) }-5-methylthiothiophene-2-carboxamidine,
4-{2-[(diphenylmethyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,
5-methylthio-4-{2-[(3-phenylpropyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine,
5-methylthio-4-{2-[(2,4,5-trimethylphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine,
4-{2-[(2-fluorophenyl)amino](1,3-thiazol-4-yl}-5-methylthiothiophene-2-carboxamidine,
4-{2-[(3-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,
4-(2-{[2-(methylethyl)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine,
5-methylthio-4-(2-{[4-(phenylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidine,
4-(2-[(2-bromophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,
4-{2-[(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,
4-{2-[(2-bromomethylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,
5-methylthio-4-{2-[(2-morpholin-4-ylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine,
4-{2-[(2,3-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,
5-methylthio-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine,
5-methylthio-4-{2-[(2-piperidylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine,
4-(2-{[(4-methylphenyl)methyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine,
4-(2-{[4-(4-chlorophenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine,
4-(2-{[4-phenoxyphenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine,
5-methylthio-4-(2-{[4-(phenylamino)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidine,
5-methylthio-4-(2-{[4-benzylphenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidine,
5-methylthio-4-(2-{[4-(piperidylsulfonyl)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidine,
5-methylthio-4-[2-(3-quinolylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidine,
5-methylthio-4-[2-(2-naphthylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidine,
4-[2-(2H-benzo[3,4-d]1,3-dioxolan-5-ylamino)(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidine,
4-(2-[(7-bromofluoren-2-yl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,
4-{2-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,
5-methylthio-4-(2-{[4-(phenyldiazenyl)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidine,
5-methylthio 4-(2-{[3-(hydroxymethyl)phenyl]amino}(1,3-thiazol-4-yl))-thiophene-2-carboxamidine,
4-[2-({3-[(3-methylpiperidyl)methyl]phenyl}amino)(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidine,
4-{2-[(3-hydroxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,
4-(2-{[4-(carbamoylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine,
5-methyl-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine,
5-methyl-4-{2-[(4-phenoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine,
5-methyl4-[2-(phenylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamnidine, and
4-(4-isoxazol-5-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;
as well as pharmaceutically acceptable salts and prodrugs thereof.
A seventh preferred group of compounds are compounds of Formula I,
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
X is sulfur or oxygen, preferably sulfur;
Y is a covalent bond or xe2x80x94NHxe2x80x94, preferably a covalent bond;
Z is NR5R6;
R1 is hydrogen, amino, hydroxy or halogen, preferably hydrogen;
R4, R5 and R6 are independently hydrogen, C1-4alkyl, amino, C1-4alkoxy or hydroxy, and are preferably all hydrogen;
R3 is hydrogen, C1-6alkylthio, C1-6alkyl optionally substituted with OH, NH2. COOH or aminocarbonyl, or C1-6alkoxy, preferably methylthio or methyl; and
R2 is
alkylsulfonylamino, aralkylsulfonylamino, aralkenylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, di(aralkylsulfonyl)amino, di(aralkenylsulfonyl)amino, di(arylsulfonyl)amino, or di-(heteroarylsulfonyl)amino, wherein any of the aryl or heteroaryl containing groups can be optionally substituted on the aromatic ring; or
amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino, monoheterocycleamino, diheterocycleamino, monoalkylmonoheterocycleamino, wherein any of the aryl or heteroaryl containing groups can be optionally substituted on the aromatic ring and wherein any of the heterocycle containing groups can be optionally ring substituted; or
alkanoylamino, alkenoylamino, alkynoylamino, aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino, heteroarylalkanoylamino, any of which is optionally substituted on the aromatic ring; or
alkoxy and alkylthio, either of which is optionally substituted, or aryloxy, aralkoxy, arylthio, aralkylthio, arylsulfonyl, aralkylsulfonyl, aralkenylsulfonyl, any of which is optionally substituted on the aromatic ring; or
alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, wherein any of the aryl containing groups can be optionally substituted on the aromatic ring; or
formylamino, H(S)CNHxe2x80x94, or thioacylamino.
Preferred optional substituents are halogen, C1-6alkyl, C1-6alkoxy, hydroxy, nitro, trifluoromethyl, C6-10aryl, C6-10aryloxy, C6-10arylmethoxy (wherein the aryl groups on these aryl-containing substituents are further optionally substituted by one or two of chloro, halogen, C1-6alkyl, C16alkoxy, phenyl, hydroxy, nitro, trifluoromethyl, carboxy, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, or amino), C1-6aminoalkyl, carboxy, alkyl, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, amino, mono- or di-(C1-6)alkylamino, mono- or di- C6-10arylamino, C1-6alkylsulfonylamino, C6-10arylsulfonylamino, C1-8acylamino, C1-8akoxycarbonyl, C1-6alkanoylamino, C6-14aroylamino, C1-6hydroxyalkyl, methylsulfonyl, phenylsulfonyl, thienyl (further optionally substituted by one or two of chloro, amino, methyl, methoxy, or hydroxy) and tetrazolyl.
In one aspect of this embodiment, R2 is preferably C1-6alkylsulfonylamino, C6-10ar(C1-6)alkylsulfonylamino, C6-10ar(C2-6)alkenylsulfonylamino, C6-10arylsulfonylamino, heteroarylsulfonylamino, di(C6-10ar(C1-16)alkylsulfonyl)amino, di(C6-10ar(C2-6)alkenylsulfonyl)amino, di(C6-10arylsulfonyl)amino, or di-(heteroarylsulfonyl)amino, wherein any of the aryl or heteroaryl containing groups can be optionally substituted on the aromatic ring.
Especially preferred R2 groups in this embodiment of the invention include C6-10arylsulfonylamino, di-(C6-10arylsulfonyl)amino, C6-10ar(C1-3)alkylsulfonylamino, di-(C6-10ar(C1-3)alkylsulfonyl)amino, thienylsulfonylamino, any of which is optionally substituted on the aromatic ring.
Useful values of R2, when R2 is a substituted sulfonylamino group include biphenylsul fonylamino, bis(biphenylsulfonyl)amino, naphth-2-ylsulfonylamino, di(naphth-2-ylsulfonyl)amino, 6-bromonaphth-2-ylsulfonylamino, di(6-bromonaphth-2-ylsulfonyl)amino, naphth-1-ylsulfonylamino, di(naphth-1-ylsulfonyl)amino, 2-methylphenylsulfonylamino, di-(2-methylphenylsulfonyl)amino, 3-methylphenylsulfonylamino, di-(3-methylphenylsulfonyl)amino, 4-methylphenylsulfonylamnino, di-(4-methylphenylsulfonyl)amino, benzylsulfonylamino, 4-methoxyphenylsulfonylamino, di-(4-methoxyphenylsulfonyl)amino, 4-iodophenylsulfonylamino, di-(4-iodophenylsulfonyl)amino, 3,4-dimethoxyphenylsulfonylamino, bis-(3,4-dimethoxyphenylsulfonyl)amino, 2-chlorophenylsulfonylamino, di-(2-chlorophenylsulfonyl)amino, 3-chlorophenylsulfonylamino, di-(3-chlorophenylsulfonyl)amino, 4-chlorophenylsulfonylamino, di-(4-chlorophenylsulfonyl)amino, phenylsulfonylamino, di-(phenylsulfonyl)amino, 4-tert-butylphenylsulfonylamino, di-(4-tert-butylphenylsulfonyl)amino, 2-phenylethenylsulfonylamino, and 4-(phenylsulfonyl)thien-2-ylsulfonylamino.
In another aspect of this embodiment, R2 is preferably amino, mono(C16)alkylamino, di(C1-6)alkylamino, mono(C6-10)arylamino, di(C6-10)arylamino, mono(C1-6)alkylmono(C6-10)arylamino, monoar(C1-6)alkylamino, di(C6-10)ar(C1-6)alkylamino, mono(C1-6)alkylmono(C6-10)ar(C1-6)alkylamino, monoheteroarylamino, diheteroarylamino, mono(C1-6)alkylmonoheteroarylamino, wherein any of the aryl or heteroaryl containing groups can be optionally substituted on the aromatic ring.
Especially preferred R2 groups in this embodiment of the invention include mono(C6-10)arylamino, mono(C1-6)alkylmono(C6-10)arylamino, mono(C6-10)ar(C1-3)alkylamino, mono(C1-6)alkylmono(C6-10)ar(C1-3)alkylamino, monoheteroarylamino, and mono(C1-6)alkylmonoheteroarylamino Examples of suitable heteroarylamino groups include 1,3-thiazol-2-ylamino, imidazol-4-ylamino, quinolin-2-ylamino and quinolin-6-ylamino.
Useful values of R2, when R2 is a substituted amino group include anilino, naphth-2-ylamino, naphth-1-ylamino, 4-(biphenyl)thiazol-2-ylamino, 4-(phenyl)thiazol-2-ylamino, 4-phenyl-5-methylthiazol-2-ylamino, 4-hydroxy-4-trifluoromethylthiazol-2-ylamino, 3-phenylphenylamino, pyrimidin-2-ylamino, 4-isopropylphenylamino, 3-isopropylphenylamino, 4-phenylphenylamino, 3-fluoro-4-phenylphenylamino, 3,4-methylenedioxyphenylamino, n-butylphenylamino, N-methyl-N-(2-methylphenyl)amino, 3-nitrophenylamino, 4-methoxyphenylamino, 3-methoxyphenylamino, 2-methoxyphenylaminno, 2-methylphenylamino, 3-methylphenyl amino, 3,4-dimethylphenylamino, 3-chlorophenylamino, 4-chlorophenylamino, 4-(3-fluoro-4-methylphenyl)amino, 4-(indan-5-yl)amino, benzylamino, indanylmethylamino, 2,3-dihydrobenzofuranylmethyl, 2-phenylimidazol-5-yl, 3-hydroxybenzyl, 3-phenoxyphenylamino, 4-phenoxyphenylamino, 3-benzyloxyphenylamino, 4-benzyloxyphenylamino, quinolin-6-ylamino, quinolin-3-ylamino, 4-(phenylamino)phenylamino, 4-(4-ethylphenyl)phenylamino, 4-(dimethylamino)phenylamino, 4-cyclohexylphenylamino, 4-(9-ethylcarbazol-3-yl)amino, 4-(t-butyl)phenylamino, and 4-methylthiophenyl amino.
In another aspect of this embodiment, R2 is preferably an acylamino group, such as alkanoylamino, alkenoylamino, aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino, heteroarylalkanoylamino, any of which is optionally substituted on the aromatic ring.
Especially preferred R2 groups in this embodiment of the invention include (C6-10)arylcarbonylamino, C6-10ar(C1-3)alkylcarbonylamino, C6-10ar(C2-3)alkenylcarbonylamino, C6-10aryloxy(C1-3)alkylcarbonylamino, C3-8cycloalkylcarbonylamino, C1-4alkylcarbonylamino, and heteroarylcarbonylamino, such as furanylcarbonylamino, and quinolinylcarbonylamino.
Useful values of R2, when R2 is an acylamino group include 3-hydroxyphenylcarbonylamino, 2-phenylethenylcarbonylamino, phenylcarbonylamino, cyclohexylcarbonylamino, 4-methyl-3-nitrophenylcarbonylamino, furan-2-ylcarbonylamino, tert-butylcarbonylamino, 5-(3,5-dichlorophenoxy)furan-2-ylcarbonylamino, naphth-1-ylcarbonylamino, quinolin-2-ylcarbonylamino, 4-ethoxyphenylcarbonylamino, phenoxymethylcarbonylamino, and 3-methylphenylcarbonylamino.
In another aspect of this embodiment, R2 is preferably C6-10aryloxy, C6-10ar(C1-6)alkoxy, C6-10arylsulfonyl, C6-10ar(C )alkylsulfonyl, or C6-10ar(C2-6)alkenylsulfonyl, any of which is optionally substituted on the aromatic ring. Especially preferred R2 groups in this embodiment of the invention include C6-10aryloxy, and C6-10arylsulfonyl.
Useful values of R2, when R2 is an aryloxy or arylsulfonyl group include phenoxy, naphthyloxy, phenylsulfonyl, and naphthylsulfonyl.
Representative compounds within the scope of this seventh embodiment of the invention include:
5-methylthio-4-(6-quinolylamino)thiophene-2-carboxamidine
5-methylthio-4-[(3-phenylphenyl)amino]thiophene-2-carboxamidine
5-methylthio-4-(3-quinolylamino)thiophene-2-carboxamidine 5-methylthio-4-(pyrimidin-2-ylamino)thiophene-2-carboxamidine
4-[(4-cyclohexylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
methyl 4-amino-5-methylthiothiophene-2-carboxylatemethyl 4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylate
5-methylthio-4-[(4-phenyl(1,3-thiazol-2-yl))amino]thiophene-2-carboxamidine
5-methylthio-4-{[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]amino}thiophene-2-carboxamidine
4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl))amino]-5-methylthiothiophene-2-carboxamidine
4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-(2-naphthylamino)thiophene-2-carboxamidine
4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine
4-[(3-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
4-[(3-methoxyphenyl)amino]-5-methylthlothiophene-2-carboxamidine
4-{[3-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxamidine
4-{[4-(methylethyl)phenyl]amino)-5-methylthiothiophene-2-carboxamidine
4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-[(4-phenylphenyl)amino]thiophene-2-carboxamidine
4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthlothiophene-2-carboxamidine
4-(2H-benzo[d]1,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-carboxamidine
4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-[benzylamino]thiophene-2-carboxamidine
4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine
4-(2,3-dihydrobenzo[b]furan-5-ylamino)-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-[(2-phenylimidazol-4-yl)amino]thiophene-2-carboxamidine
5-methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxamidine
4-{[(3-hydroxyphenyl)methyl]amino}-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-(phenylcarbonylamino)thiophene-2-carboxamidine
4-((2E)-3-phenylprop-2-enoylamino)-5-methylthiothiophene-2-carboxamidine
4-[(4-chlorophenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine
4-(cyclohexylcarbonylamino)-5-methylthiothiophene-2-carboxamidine methyl 4-[(4-methyl-3-nitrophenyl)carbonylamino]-5-methylthiothiophene-2-carboxylate
4-(2-furylcarbonylamino)-5-methylthiothiophene-2-carboxamidine
4-(2,2-dimethylpropanoylamino)-5-methylthiothiophene-2-carboxamidine
4-[5-(3,5-dichlorophenoxy)(2-furyl)]carbonylamino)-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-(naphthylcarbonylamino)-thiophene-2-carboxamidine
5-methylthio-4-(2-quinolylcarbonyl-amino)thiophene-2-carboxamidine
4-[(3-methoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine
4-[2-(2-hydroxy-5-methoxyphenyl)acetylamino]-5-methylthiothiophene-2-carboxamidine
4-[(4-ethoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-(2-phenoxyacetylamino)-thiophene-2-carboxamidine
4-[(3-methylphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-[3-(phenylmethoxy)phenyl]amino}thiophene-2-carboxamidine
5-methylthio-4-[(3-phenoxyphenyl) amino)thiophene-2-carboxamidine
5-methylthio-4-[(4-phenoxyphenyl)amino]thiophene-2-carboxamidine
4-[(2-methoxyphenyl)amino]-5-methylthiothlophene-2-carboxamidine
4-[(2-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
4-[(3-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine
4-(methylphenylamino)-5-methylthiothiophene-2-carboxamidine
5-methyl-4-(phenylamino)thiophene-2-carboxamidine
4-{4-(dimethylamino)phenyl]amino}-5-methylthiothiophene-2-carboxamidine
4-[(4-ethylphenyl)amino) ]-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-{[4-(phenylmethoxy)phenyl]amino}thiophene-2-carboxamidine
5-methylthio-4-{[4-(phenylamino)phenyl]amino}thiophene-2-carboxamidine
4-[(4-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine
4-[(3-fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine
4-[(9-ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-{[(4-phenylphenyl)sulfonyl]amino}thiophene-2-carboxamidine
4-{bis[(4-phenylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-[(2-naphthylsulfonyl)-amino]thiophene-2-carboxamidine
4-[bis(2-naphthylsulfonyl)amino]-5-methylthiothiophene-2-carboxamidine
4-{[(6-bromo(2-naphthyl))sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine
4-{bis[(6-bromo(2-naphthyl))sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-[(naphthylsulfonyl)-amino]thiophene-2-carboxamidine
4-[bis(naphthylsulfonyl)amino]-5-methylthiothiophene-2-carboxamidine
4-{[(2-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine
4-{bis[(2-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine
4-{[(3-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine
4-{bis[(3-methylphenyl)sulfonyl]amino}-5-methylthiothiophene -2-carboxamidine
4-{[(4-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine
4-{bis[(4-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-{[benzylsulfonyl]amino}-thiophene-2-carboxamidine
5-methylthio-4-phenoxythiophene-2-carboxamidine
5-methylthio-4-(phenylsulfonyl)thiophene-2-carboxamidine
as well as salts thereof, such as hydrochloride or trifluoracetate salts and prodrugs thereof.
For medicinal use, the pharmaceutically acceptable acid addition salts, those salts in which the anion does not contribute significantly to toxicity or pharmacological activity of the organic cation, are preferred. The acid addition salts are obtained either by reaction of an organic base of Formula I with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods detailed in the literature available to any practitioner skilled in the art. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, cyclamic acid, pivalic acid and the like; useful inorganic acids are hydrohalide acids such as HCl, HBr, HI; sulfuric acid; phosphoric acid and the like. Preferred acids for forming acid addition salts include HCl and acetic acid.
The compounds of the present invention represent a novel class of potent inhibitors of metallo, acid, thiol and serine proteases. Examples of the serine proteases inhibited by compounds within the scope of the invention include leukocyte neutrophil elastase, a proteolytic enzyme implicated in the pathogenesis of emphysema; chymotrypsin and trypsin, digestive enzymes; pancreatic elastase, and cathepsin G, a chymotrypsin-like protease also associated with leukocytes; thrombin and factor Xa, proteolytic enzymes in the blood coagulation pathway. Inhibition of thermolysin, a metalloprotease, and pepsin, an acid protease, are also contemplated uses of compounds of the present invention. The compounds of the present invention are preferably employed to inhibit trypsin-like proteases.
Compounds of the present invention that inhibit urokinase plasminogen activator are potentially useful in treating excessive cell growth disease state. Compounds of the present that inhibit urokinase are, therefore, useful as anti-angiogenic, anti-arthritic, anti-inflammatory, anti-invasive, anti-metastatic, anti-restenotic, anti-osteoporotic, anti-retinopathic (for angiogenesis-dependent retinopathies), contraceptive, and tumoristatic treatment agents. For example, such treatment agents are useful in the treatment of a variety of disease states, including but not limited to, benign prostatic hypertrophy, prostatic carcinoma, tumor metastasis, restenosis and psoriasis. Also provided are methods to inhibit extracellular proteolysis, methods to treat benign prostatic hypertrophy, prostatic carcinoma, tumor metastasis, restenosis and psoriasis by administering the compound of Formula I. For their end-use application, the potency and other biochemical parameters of the enzyme inhibiting characteristics of compounds of the present invention are readily ascertained by standard biochemical techniques well known in the art. Actual dose ranges for this application will depend upon the nature and severity of the disease state of the patient or animal to be treated as determined by the attending diagnostician. It is to be expected that a general dose range will be about 0.01 to 50 mg, preferably 0.1 to about 20 mg per kg per day for an effective therapeutic effect.
An end use application of the compounds that inhibit chymotrypsin and trypsin is in the treatment of pancreatitis. For their end-use application, the potency and other biochemical parameters of the enzyme-inhibiting characteristics of the compounds of the present invention is readily ascertained by standard biochemical techniques well known in the art. Actual dose ranges for their specific end-use application will, of course, depend upon the nature and severity of the disease state of the patient or animal to be treated, as determined by the attending diagnostician. It is expected that a useful dose range will be about 0.01 to about 50 mg, preferably about 0.1 to about 20 mg per kg per day for an effective therapeutic effect.
Compounds of the present invention that are distinguished by their ability to inhibit either factor Xa or thrombin may be employed for a number of therapeutic purposes. As factor Xa or thrombin inhibitors, compounds of the present invention inhibit thrombin production. Therefore, these compounds are useful for the treatment or prophylaxis of states characterized by abnormal venous or arterial thrombosis involving either thrombin production or action. These states include, but are not limited to, deep vein thrombosis; disseminated intravascular coagulopathy which occurs during septic shock, viral infections and cancer; myocardial infarction; stroke; coronary artery bypass; fibrin formation in the eye; hip replacement; and thrombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PCTA).
By virtue of the effects of both factor Xa and thrombin on a host of cell types, such as smooth muscle cells, endothelial cells and neutrophils, the compounds of the present invention find additional use in the treatment or prophylaxis of adult respiratory distress syndrome; inflammatory responses; wound healing; reperfusion damage; atherosclerosis; and restenosis following an injury such as balloon angioplasty, atherectomy, and arterial stent placement. The compounds of the present invention may be useful in treating neoplasia and metastasis as well as neurodegenerative diseases, such as Alzheimer""s disease and Parkinson""s disease.
When employed as thrombin or factor Xa inhibitors, the compounds of the present invention may be administered in an effective amount within the dosage range of about 0.1 to about 500 mg/kg, preferably between 0.1 to 30 mg/kg body weight, on a regimen in single or 2-4 divided daily doses.
Human leucocyte elastase is released by polymorphonuclear leukocytes at sites of inflammation and thus is a contributing cause for a number of disease states. Compounds of the present invention are expected to have an anti-inflammatory effect useful in the treatment of gout, rheumatoid arthritis and other inflammatory diseases, and in the treatment of emphysema. The leucocyte elastase inhibitory properties of compounds of the present invention are determined by the method described below. Cathepsin G has also been implicated in the disease states of arthritis, gout and emphysema, and in addition, glomerulonephritis and lung infestations caused by infections in the lung. In their end-use application the enzyme inhibitory properties of the compounds of Formula I is readily ascertained by standard biochemical techniques that are well-known in the art.
The Cathepsin G inhibitory properties of compounds within the scope of the present invention are determined by the following method. A preparation of partially purified human Cathepsin G is obtained by the procedure of Baugh et al., Biochemistry 15: 836 (1979). Leukocyte granules are a major source for the preparation of leukocyte elastase and cathepsin G (chymotrypsin-like activity). Leukocytes are lysed and granules are isolated. The leukocyte granules are extracted with 0.20 M sodium acetate, pH 4.0, and extracts are dialyzed against 0.05 M Tris buffer, pH 8.0 containing 0.05 M NaCl overnight at 4xc2x0 C. A protein fraction precipitates during dialysis and is isolated by centrifugation. This fraction contains most of the chymotrypsin-like activity of leukocyte granules. Specific substrates are prepared for each enzyme, namely N-Suc-Ala-Ala-Pro-Val-p-nitroanilide and Suc-Ala-Ala-Pro-Phe-p-nitroanilide. The latter is not hydrolyzed by leukocyte elastase. Enzyme preparations are assayed in 2.00 mL of 0.10 M Hepes buffer, pH 7.5, containing 0.50 M NaCl, 10% dimethylsulfoxide and 0.0020 M Suc-Ala-Ala-Pro-Phe-p-nitroanilide as a substrate. Hydrolysis of the p-nitroanilide substrate is monitored at 405 nm and at 25xc2x0 C.
Useful dose range for the application of compounds of the present invention as neutrophil elastase inhibitors and as Cathepsin G inhibitors depend upon the nature and severity of the disease state, as determined by the attending diagnostician, with a range of 0.01 to 10 mg/kg body weight, per day, being useful for the aforementioned disease states.
Additional uses for compounds of the present invention include analysis of commercial reagent enzymes for active site concentration. For example, chymotrypsin is supplied as a standard reagent for use in clinical quantitation of chymotrypsin activity in pancreatic juices and feces. Such assays are diagnostic for gastrointestinal and pancreatic disorders. Pancreatic elastase is also supplied commercially as a reagent for quantitation of xcex11-antitrypsin in plasma. Plasma xcex11-antitrypsin increases in concentration during the course of several inflammatory diseases, and xcex11-antitrypsin deficiencies are associated with increased incidence of lung disease. Compounds of the present invention can be used to enhance the accuracy and reproducibility of these assays by titrametric standardization of the commercial elastase supplied as a reagent. See, U.S. Pat. No. 4,499,082.
Protease activity in certain protein extracts during purification of particular proteins is a recurring problem which can complicate and compromise the results of protein isolation procedures. Certain proteases present in such extracts can be inhibited during purification steps by compounds of the present invention, which bind tightly to various proteolytic enzymes.
The pharmaceutical compositions of the invention can be administered to any animal that can experience the beneficial effects of the compounds of the invention. Foremost among such animals are humans, although the invention is not intended to be so limited.
The pharmaceutical compositions of the present invention can be administered by any means that achieve their intended purpose. For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular routes. Alternatively, or concurrently, administration can be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
In addition to the pharmacologically active compounds, the new pharmaceutical preparations can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
The pharmaceutical preparations of the present invention are manufactured in a manner that is, itself, known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
Suitable excipients are, in particular, fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents can be added, such as, the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as, sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as, magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings that, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as, acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as, glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules that may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as, fatty oils or liquid paraffin. In addition, stabilizers may be added.
Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, alkaline solutions and cyclodextrin inclusion complexes. Especially preferred salts are hydrochloride and acetate salts. One or more modified or unmodified cyclodextrins can be employed to stabilize and increase the water solubility of compounds of the present invention. Useful cyclodextrins for this purpose are disclosed in U.S. Pat. Nos. 4,727,064, 4,764,604, and 5,024,998.
In addition, suspensions of the active compounds as appropriate oily injection suspensions can be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.
Many synthetic methods used to form compounds of the present invention generally involve the formation of an amidine from a carboxylic acid derivative, such as an ester or a nitrile. In the process a Lewis acid, such as trimethylaluminum, is added to a source of ammonia, such as ammonium chloride in an aprotic solvent, such as a toluene, under an inert atmosphere (e.g., under an atmosphere of nitrogen or argon gas) at a temperature between xe2x88x9215xc2x0 C. and 5xc2x0 C., preferably at 0xc2x0 C. An appropriate carboxylic acid derivative is added to the mixture and the mixture is heated at reflux for a predetermined period of time, preferably between 1 hr. and 24 hrs., and most preferably between 1 hr. and 4 hrs. The resulting solution is allowed to cool to room temperature and the amidine product isolated by known methods.
The chemical schemes appear after the description of the schemes.
Scheme 1a illustrates a general approach to compounds of Formula I where X=O or S, R3=alkylthio, aralkylthio, arylthio, alkyloxy, aralkyloxy or aryloxy, Y=bond and Z=NR5R6. When R22 and R21 of compounds 2 and 3 are retained in the final product, they correspond to R2 and R3 of Formula I, respectively. Otherwise R22 and R21 represent groups which, after further transformations, will become R2 and R3 of Formula I.
Starting with the heterocycle where X=O or S appropriately substituted by two leaving groups, the leaving groups can be sequentially displaced by appropriate nucleophiles (preferably the anion of the group R21 or R22 to be substituted) to produce the mono- or disubstituted heterocycles. Examples of leaving groups include halogens (chlorine, bromine or iodine), sulfonates (methanesulfonate, toluenesulfonate or trifluoromethanesulfonate) or sulfones (methylsulfonyl). Preferable nucleophiles include anions of thiols or alcohols having as the counterion an alkali or alkali earth metal such as sodium, lithium, potassium, magnesium or cesium, or in some cases, a transition group metal such as zinc, copper or nickel. In certain cases where the nucleophile used contains an anion on carbon, catalysis of the displacement may be useful for this transformation. Examples of catalysts would include compounds containing palladium, silver or Ni salts.
Scheme 1b illustrates approaches to providing the functionality of Y(CNR4)Z in compounds of Formula I where X=N, O or S, R22 and R21 are defined as in Scheme 1a. Depending on the nature of the group W in 3, several methods may be employed in the transformation of W to Y(CNR4)Z.
When W in 3 is a cyano group (CN), primary amide (CONH2) or ester (CO2R23), direct conversion to an unsubstituted amidine 5 (i.e. Formula I where Y=bond, Z=NR5R6 and R4, R5, R6=H) can be effected by treatment with a reagent consisting of a Lewis acid complexed to ammonia. This complex is produced by treatment of ammonia or an ammonium salt, preferably an ammonium halide and most preferably ammonium chloride or bromide, with an appropriate Lewis acid, preferably a trialkylaluminum and most preferably trimethyl- or triethylaluminum in a solvent inert to the Lewis acid employed. For example, when a trialkylaluminum Lewis acid is employed with an ammonium halide, reaction occurs with loss of one equivalent of alkane to produce the dialkylhaloaluminum complex of ammonia (see for example Sidler, D. R., et al, J. Org. Chem., 59:1231 (1994)). Examples of suitable solvents include unsaturated hydrocarbons such as benzene, toluene, xylenes, or mesitylene, preferably toluene, or halogenated hydrocarbons such as dichloroethane, chlorobenzene or dichlorobenzene. The amidination reaction is generally carried out at elevated temperatures, preferably 40-200 xc2x0 C., more preferably 80-140xc2x0 C., and most preferably at the reflux temperature of a solvent in the range of 80-120xc2x0 C.
When W is a cyano group (CN), direct conversion to a mono- or disubstituted amidine 5 (R4, R5, R6=H) is also possible by treatment with a reagent consisting of a Lewis acid, preferably a trialkylaluminum, complexed to a mono- or disubstituted amine H2NR5 or HNR5R6 (Garigipati, R., Tetrahedron Lett. 31: 1969 (1990)). Alternatively the same addition of a mono- or disubstituted amine may catalyzed by a copper salt such as Cu(I) chloride (Rousselet, G., et al, Tetrahedron Lett. 34: 6395 (1993)).
When W in 3 is a carboxyl group (CO2H), indirect conversion to an unsubstituted amidine 5 can be carried out by initial esterification to 4 by any of a number of well-known dehydrating agents (for example, dicyclohexylcarbodiimide) with an alcohol (R23OH). More preferably 4 can be made by initial formation of an acid chloride by treatment of 3 with any of a number of anhydrides of HCl and another acid, such as thionyl chloride, POCl3, PCl3, PCl5, or more preferably oxalyl chloride, with or without an added catalyst such as N,N-dimethylformamide (DMF), followed by the alcohol R23OH. Conversion to the unsubstituted amidine 5 (R4, R5, R6=H) can be carried out by treatment with a Lewis acid complexed to ammonia.
Amidines 5 also can be produced indirectly by conversion of 3 (W=CN) to iminoethers 6 by exposure to a strong acid such as a hydrogen halide, HBF4 or other non-nucleophilic acid, preferably gaseous HCl in the presence of an alcohol R23OH (R23=alkyl, branched alkyl or cycloalkyl, preferably Me or Et) and most preferably with the alcohol as solvent. Alternatively when W=CONH2, conversion to an iminoether can be carried out by treatment with a trialkyloxonium salt (Meerwein""s salts). In either case, treatment of the iminoether 6 with ammonia (R5, R6=H) or a mono- or disubstituted amine (HNR5R6) provides the corresponding unsubstituted or substituted amidines 5 (i.e. via classical Pinner synthesis: Pinner, A., Die Iminoaether und ihre Derivate, Verlag R. Oppenheim, Berlin (1892)).
When W=NH2 in 3, treatment with a reagent Z(CNR4)L where Z=alkyl and L is a leaving group such as O-alkyl and preferably OMe, provides the subclass of amidines 135 (Z=alkyl ) which are isomeric to 5 (Formula I, where Y=NH, Z=H or alkyl). Examples of reagents for this reaction include methyl or ethyl acetimidate hydrochloride. Alternatively treatment of 3 (W=NH2) with a trialkyl orthoformate ester, preferably trimethyl- or triethyl orthoformate, followed by an amine R4NH2 affords the corresponding formidines 135 (Z=H) (Formula I, where Y=NH, Z=H).
Also, when W=NH2, 3 can be treated with a reagent Z(CNR4)L where R4=H and Z=NR5R6 and L is a leaving group such as pyrazole, methylpyrazole, SO3H, S-alkyl, S-aryl, trifluoromethanesulfonate (OTf) or trifluoromethanesulfonamide (NHTf), preferably pyrazole, SO3H or trifluoromethanesulfonamide (NHTf). Examples of these reagents include aminoiminosulfonic acid (Miller, A. E. and Bischoff, J. J., Synthesis, 777 (1986) and 1H-pyrazole-1-carboxamidine hydrochloride (Bernatowicz, M. S., et al., J. Org. Chem. 57:2497 (1992)). Such treatment provides guanidines 136 directly (Formula I where Y=NH, Z=NR5R6). Alternatively a reagent Z(CNP1)L may be also used where Z=NHP2 and L again a leaving group such as pyrazole, methylpyrazole, SO3H, S-alkyl, S-aryl, trifluoromethanesulfonate (OTf) or trifluoromethanesulfonamide (NHTf), to provide protected guanidines (P1, p2=alkoxylcarbonyl, aralkoxycarbonyl or polymer-bound alkoxylcarbonyl similar to those described below in Scheme 4a) where the protecting groups P1 and P2 can then be removed to give unsubstituted 136 (R4, R5 and R6=H). Protected guanidines are advantageous when further transformations are required after introduction of the guanidine functionality where an unprotected guanidine would not be stable. Examples of these protected reagents include reagents such as N,Nxe2x80x2-bis(tert-butoxycarbonyl)-S-methylthiourea (Bergeron, R. J. and McManis, J. S, J. Org. Chem. 52:1700 (1987)), N,Nxe2x80x2-bis(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine or N,Nxe2x80x2-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (Bernatowicz, M. S., et al., Tetrahedron Letters, 34: 3389 (1993)), N,Nxe2x80x2-bis(benzyloxycarbonyl)-Nxe2x80x3-trifluoromethanesulfonylguanidine, and N,Nxe2x80x2-bis(bis(tert-butoxycarbonyl)-Nxe2x80x3-trifluoromethanesulfonylguanidine (Feichtinger, K., et al, J. Org. Chem. 63:3804 (1998)). Detailed descriptions and examples of these protecting groups and their use as protection for amidines are further outlined in Schemes 4a, 4b and 5.
When W in 3 is an ester (CO2R23) or carboxyl group (CO2H), indirect conversion to an N-substituted or unsubstituted methylarmidine (Formula I where Y=CH2, Z=NR5R6) can be carried out by initial reduction of the ester or carboxyl by any of a number of well-known reducing agents. When W in 3 is an ester (CO2R23), examples of reducing agents include reducing agents such lithium aluminum hydride (LAH) and lithium borohydride. When W in 3 is a carboxyl group (CO2H), examples of reducing agents include LAH and borane complexed to THF, dimethyl sulfide, dimethylamine or pyridine. The resulting hydroxymethyl derivative (W=CH2OH) is converted to a cyanomethyl derivative (W=CH2CN) by initial formation of a leaving group (W=CH2L) where the leaving group L is a halogen (chlorine, bromine or iodine) or sulfonate ester (for example methanesulfonate, toluenesulfonate or trifluoromethanesulfonate). Displacement of L by cyanide can then be performed by treatment with a metal cyanide such as LiCN, NaCN, KCN or CuCN in a polar solvent such as DMF and with or without a catalyst such as a crown ether, to afford the cyanomethyl derivative (see for example Mizuno, Y., et al, Synthesis, 1008 (1980)). More preferably, the conversion of W=CH2OH to W=CH2CN may be effected by a Mitsunobu reaction (Mitsunobu, O., Synthesis, 1 (1981)) using an azodicarboxylate ester such as diethyl azodicarboxylate or diusopropyl azodicarboxylate, Ph3P and a source of cyanide such as HCN or more preferably acetone cyanohydrin (Wilk, B. Synthetic Commun. 23:2481 (1993)). Treatment of the resulting cyanomethyl intermediate (W=CH2CN) under the conditions described for the conversion of 3 (W=CN) to 5 (either directly or indirectly via 6) provides the corresponding amidinomethyl products.
When not commercially available, alkylthiothiophenes (3, X=S, R1OH or NH2, R12=SR54, W=CN, CO2R23, CONH2) can be synthesized by the methods illustrated in Scheme 1c. Condensation of carbon disulfide and a malonic acid derivative (R52CH2R22) in the presence of two alkylating agents R54L and WCH2L and a base in a suitable medium provide 3 (Dolman, H., European Patent Application No. 0 234 622 A1 (1987)). When R22=R52=CN, the resulting R1 will be NH2; when R22=R52=CO2R23, the resulting R1 will be OH; and when R22 and R52=CN, CO2R23, the resulting R1 can be selected to be OH or NH2 (and R22=CN or CO2R23) depending on the reaction conditions and order of reagent addition. Examples of malonic acid derivatives suitable for this transformation include but are not limited to malonate diesters such as dimethyl malonate or diethyl malonate (R52, R22=CO2R23, R23=Me or Et), malononitrile (R52, R22=CN), or methyl or ethyl cyanoacetate (R52=CO2R23, R22=CN, R23=Me or Et). Leaving groups L include halides such as chloride, bromide or iodide, preferably bromide or iodide, or sulfonates such as toluenesulfonate, benzenesulfonate, methanesulfonate or trifluoromethanesulfonate. Examples of alkylating agent R54L include primary or secondary alkyl, allyl or aralkyl halides or sulfonates, such as methyl iodide, isopropyl bromide, allyl bromide, benzyl chloride or methyl trifluoromethanesulfonate, or a 2-haloacetate ester such as tert-butyl 2-bromoacetate. Examples of alkylating agents WCH2L include 2-chloroacetonitrile, methyl 2-bromoacetate or 2-bromoacetamide. Suitable media are generally polar aprotic solvents, for example, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP) or dimethylsulfoxide (DMSO), preferably DMF.
Alternatively compounds 3 (R22=CN) can be synthesized from precursors 138 (derived from malononitrile, R54L and carbon disulfide), a thioglycolate WCHSH and a base in a suitable polar solvent, preferably methanol (Tominaga, Y., et al, J. Heterocyclic Chem. 31:771 (1994)).
When 3 contains an amino group at R1, it can be diazotized with subsequent loss of nitrogen to give 3, R1=H by treatment with a nitrosating agent in suitable solvent. Nitrosating agents include nitrosonium tetrafluoroborate, nitrous acid or, more preferably and alkyl nitrite ester such as tert-butyl nitrite. Suitable solvents are those which are stable to the nitrosating agents, preferably DMF, benzene or toluene.
When not commercially available, heterocyclic precursors 1 or 2 (X=O, S; W=CO2R23, COOH; L=halogen) used in Scheme 1a can be synthesized by the methods illustrated in Scheme 1d. Depending on the conditions used, treatment of compounds such as 139 with elemental halogen (Cl2, Br2 or I2, preferably Br2) or an N-halosuccinimide reagent, preferably N-bromosuccinimide (NBS), affords either 1 or 2 directly. Description of suitable solvents and conditions to selectively produce 1 or 2 are found in Karminski-Zamola, G. et al, Heterocycles 38:759 (1994); Divald, S., et al, J. Org. Chem. 41:2835 (1976); and Bury, P., et al, Tetrahedron 50:8793 (1994).
Scheme 2a illustrates the synthesis of compounds 12 representing the subclass of compounds for which R2 is Formula II, where Ar=2-thiazolyl, Y=bond and Z=NR5R6. Starting with compound 1 (L=Br) and using the sequential displacement methodology discussed for Scheme 1a, R21 can be first introduced to give 7. This is followed by a second displacement with a metal cyanide such as copper (I) cyanide, sodium cyanide or lithium cyanide and most preferably copper (I) cyanide at a temperature of 80-200xc2x0 C. and preferably at 100-140xc2x0 C., in a polar aprotic solvent, preferably DMF or DMSO, to give 8. After esterification by any of the means described for the conversion of 3 to 4, conversion to the thioamide is carried out by treatment of the nitrile with any of the methods well known in the art (see for example Ren, W., et al., J. Heterocyclic Chem. 23:1757 (1986) and Paventi, M. and Edward, J. T., Can. J. Chem. 65:282 (1987)). A preferable method is treatment of the nitrile with hydrogen sulfide in the presence of a base such as a trialkyl or heterocyclic amine, preferably triethylamine or pyridine, in a polar solvent such as acetone, methanol or DMF and preferably methanol. Conversion to the thiazole can be executed by classical Hantzsch thiazole synthesis followed by amidine formation as discussed in Scheme 1b.
Scheme 2b illustrates the synthesis of compounds representing the subclass of compounds for which R2 is Formula II where, in addition to being an alternate route to Ar=2-thiazolyl (20) (see 12, Scheme 2a) also provide compounds of Formula II where Ar=2-oxazolyl (16) or 2-imidazolyl (18) (Y=bond and Z=NR5R6). Starting with compound 9, a selective hydrolysis of the nitrile with a tetrahalophthalic acid, preferably tetrafluoro- or tetrachlorophthalic acid, can be used to give 7 according to the method of Gribble, G. W. et al., Tetrahedron Lett. 29: 6557 (1988). Conversion to the acid chloride can be accomplished using the procedures discussed for conversion of 3 to 4, preferably with oxalyl chloride in dichloromethane in the presence of a catalytic amount of DMF. Coupling of the acid chloride to an aminoketone (R26COCH(R27)NH2) can be performed in the presence of an acid scavenger, preferably N,N-diisopropylethylamine (DIEA) or pyridine in a suitable solvent such as DMF, dichloromethane or tetrahydrofuran (THF) to afford the common intermediate 14. Alternatively coupling of the acid chloride to a less-substituted aminoketone (R26COCH2NH2) can be used followed by optional alkylation with alkylating agent R27L in the presence of a base, preferably NaH or t-BuOK. Transformation of 14 to the corresponding 2-oxazolyl (15), 2-imidazolyl (17) or 2-thiazolyl (19) esters can carried out by the methodology of Suzuki, M., et al., Chem. Pharm. Bull. 34:3111 (1986) followed by amidination according to Scheme 1b. In addition, direct conversion of ketoamide 14 to imidazolyl derivative 18 is possible under the same conditions for conversion of 17 to 18 when conducted for extended periods, preferably greater than 2 h.
Scheme 2c describes a general route to the synthesis of oxazoles, imidazoles and thiazoles of structure 27, 29 and 31 respectively. Acid 2 (see Scheme 1a) is converted to the ester by methods that are well known in the art (Theodora W. Greene and Peter G. M. Wuts, John Wiley and Sons, Inc. 1991). For example methyl ester 21 is formed by treating the acid in an appropriate solvent such as methanol with trimethylsilyldiazomethane. Alternatively the acid is treated with oxalyl chloride and catalytic amounts of dimethylformamide (DMF) in an appropriate solvent such as dichloromethane to form the acid chloride, which is then treated with methanol to give the methyl ester. Ester 21 is treated with a palladium (0) catalyst such as palladium tetrakistriphenylphosphine, and an alkylstannane such as hexa-n-butyldistannane or tri-n-butyltin chloride in an appropriate solvent such as DMF at elevated temperatures (50xc2x0 C.-120xc2x0 C.) to give the arylstannane of general structure 22 (Stille, J. K., Angew. Chem. Int. Ed. Engl. 25:508-524 (1986)). The stannane 22 is then treated with acid chlorides in the presence of a palladium(0) catalyst to give ketone 23. The ketone is treated with ammonia/ammonium chloride to give amine 24. Alternatively the ketone is reacted with an azide such as sodium azide in a suitable solvent such as DMF, and the resulting azidoketone is reduced to amine 23 with a suitable reducing agent such as catalytic hydrogenation in the presence of palladium on carbon and an acid such as HCl (Chem. Pharm. Bull. 33:509-514 (1985)). Ketoamides 25 are formed by coupling the ketoamine 24 with a variety of suitably functionalized acid chlorides. Alternatively amide coupling may be performed using any of a number of peptide coupling reagents such as 1,3-dicyclohexylcarbodiimide (Sheehan, J. C. et al., J. Am. Chem. Soc., 77:1067 (1955)) or Castro""s reagent (BOP, Castro, B., et al., Synthesis 413 (1976)). In another approach, amides 25 are formed directly from ketones 23 by reacting with various amide salts in an appropriate solvent such as DMF. The amide salts are generated by treating the amides with a suitable base such as sodium hydride (NaH). For example acetamide is treated with NaH in DMF at 0xc2x0 C. to give sodium acetamide. Keto amide 25 is cyclized to the oxazole 26, imidazole 28 and thiazole 30 using procedures similar to that shown in scheme 2b. Oxazole 26, imidazole 28 and thiazole 30 are treated with trimethylaluminum and ammonium chloride in refluxing toluene to give the amidines 27, 29 and 31 respectively.
Scheme 2d illustrates to the preparation of compounds of Examples 42-43, where R21 and R43 correspond in Formula I to groups R3 and R2, respectively. The acids 2 can be converted to the stannane by treatment with base, such as n-butyl lithium or sec-butyl lithium, followed by trimethyltin chloride. The resulting acid can be then converted to the ester 22 by methods that are well known in the art (Theodora W. Greene and Peter G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley and Sons, Inc. 1991). For example the methyl ester can be made by treating the acid 2 in a suitable solvent such as methanol with trimethylsilyldiazomethane. The stannane 22 can be reacted with suitable halides in the presence of catalytic amounts of a palladium catalyst, such as palladium tetrakistriphenylphosphine, to give the esters 32 (Stille, J. K., Angew. Chem. Int. Ed. Engl. 25:508-524 (1986)). These esters are then treated with trimethylaluminum and ammonium chloride in refluxing toluene to give the amidines 33. In the case where R43Ln (n=2), this can be cross-coupled to an aryl, heteroaryl or vinyl boronic acid or ester to give compounds 34 (Miyaura, N. and Suzuki, A., Chem. Rev. 95:2457-2483 (1995)). This can usually be done in the presence of catalytic amounts of a palladium (0) catalyst such as tetrakistriphenylphosphine palladium and a base such as potassium carbonate in DMF at 90xc2x0 C. Similar cross-coupling reactions can also be achieved by using aryl, heteroaryl and vinyl stannanes instead of boronic acids or esters. These esters are converted to the amidines 35 in the manner previously described.
Scheme 2e represents a modification to the methodology outlined in Scheme 2b which allows synthesis of compounds of Formula II where Ar=2-thiazolyl, 2-oxazolyl or 2-imidazolyl (Y=bond and Z=NR5R6) but which are regioisomeric to 16, 18 or 20 in the relative positions of substituents R26 and R27. This is illustrated in Scheme 2b by the synthesis of 2-oxazolyl derivative 39. Thus, acid 13 can be coupled to an hydroxy-containing amine R27CH(NH2)CH(R26)OH to give amide 36 by any of a number of amide coupling reagents well known in the art (see Bodanszky, M. and Bodanszky, A., The Practice of Peptide Synthesis, Springer-Verlag, New York (1984)). More preferably 13 can be converted to the corresponding acid chloride using any of the procedures mentioned for conversion of 3 to 4 followed by treatment with the R27CH(NH2)CH(R26)OH in the presence of an acid scavenger, preferably N,N-diisopropylethylamine (DIEA) or pyridine in a suitable solvent such as DMF, dichloromethane or tetrahydrofuran (THF) to give 36. Oxidation of the alcohol 36 to the aldehyde 37 (R26=H) or ketone 37 (R26=alkyl, aryl, aralkyl, heterocycle) can be effected by any of a number of common methods known in the art (see for example F. Carey, F. A., Sundberg, R. J. Advanced Organic Chemistry, Part B: Reactions and Synthesis, 3rd Edition, Plenum Press, New York (1990)), preferably by a mild Moffatt-type oxidation such as a Swern oxidation (Mancuso, A. J., Huang, S. L. and Swern, D., J. Org. Chem. 3329 (1976)) or more preferably using Dess-Martin reagent (Dess, D. B. and Martin, J. C., J. Org. Chem. 48:4155 (1983)). Conversion to the heterocycle (in this case the oxazole) is effected with any of a number of reagents including phosphorus oxychloride, P2O5 or thionyl chloride (see Moriya, T., et al., J. Med. Chem. 31:1197 (1988) and references therein). Alternatively closure of 37 with either Burgess reagent or under Mitsunobu conditions affords the corresponding oxazolinyl derivatives (Wipf, P. and Miller, C. P., Tetrahedron Lett. 3: 907 (1992)). Final amidination to 39 as in Scheme 1b completes the synthesis.
Scheme 2f illustrates a general approach to the synthesis of thiazoles of structure 43 (Formula II, X=S, Ar=thiazolyl). Nitriles of structure 40 can be treated with hydrogen sulfide (H2S) in a suitable solvent such as methanol, or pyridine in the presence of a base such as triethylamine to give thioamides 41 (Ren, W. et al., J. Heterocyclic Chem. 23:1757-1763 (1986)). Thioamides 41 can be then treated with various haloketones 42 preferably bromoketones under suitable reaction conditions such as refluxing acetone or DMF heated to 50xc2x0 C.-80xc2x0 C. to form the thiazoles 43 (Hantzsch, A. R. et al., Ber. 20:3118 (1887)).
Scheme 2g illustrates one synthetic route to 2-haloketones of structure 42 which are employed in the synthesis of thiazolyl derivatives as in Schemes 2a and 2f. 2-Bromoketones 42 (L=Br) are prepared by treating the ketone 44 with a suitable brominating agent such as Br2 or N-bromosuccinimide in a suitable solvent such as chloroform or acetic acid (EP 0393936 A1).
Alternatively, the ketone 44 is treated with a polymer-supported brominating agent such as poly(4-vinyl)pyridinium bromide resin (Sket, B., et al., Synthetic Communications 19:2481-2487 (1989)) to give bromoketones 42. In a similar fashion 2-chloroketones are obtained by treating 44 with copper (II) chloride in a suitable solvent such as chloroform (Kosower, E. M., et al., J. Org. Chem. 28:630 (1963)).
Scheme 2h illustrates another synthetic route to 2-haloketones of structure 42 which is particularly useful in that it employs acids 45 or activated carbonyl compounds such as 46 as precursors which are more readily available than the ketones 44. The acid 45 is converted to the acid halide 46 (L=Cl, Br or OCOR39) by treating with a suitable halogenating reagent. For example, an acid chloride is formed by treating 45 with oxalyl chloride and catalytic amounts of DMF in dichloromethane. The acid chloride is converted to a diazoketone by treatment with trimethysilyldiazomethane (Aoyama, T. et al., Tetrahedron Lett. 21:4461-4462 (1980)). The resulting diazoketone is converted to a 2-haloketone of structure 42 by treatment with a suitable mineral acid. For example a bromoketone is formed by treating the diazoketone in a suitable solvent such as acetonitrile (CH3CN) with a solution of 30% hydrogen bromide (HBr) in acetic acid (Organic Synthesis Collective Vol III, 119, John Wiley and Sons, New York, Ed. Horning E. C.). In an alternative approach the acid 45 is converted to the mixed-anhydride 46 by treatment with a suitable chloroformate such as isobutyl chloroformate or tert-butyl chloroformate in a suitable solvent, such as tetrahydrofuran or dichloromethane, in the presence of a base such as N-methylmorpholine. The mixed anhydride 46 is converted to a diazoketone by treatment with trimethylsilyldiazomethane and the resulting diazoketone is converted to a haloketone in the manner described above.
When amide coupling as described in Scheme 2e is followed directly by amidination, compounds of Formula I where R2 or R3 is aminoacyl or aminoiminomethyl can be derived. Thus, coupling of acid 13 (or the corresponding acid chloride as previously described) with an amine R51R52NH can afford 130 which can be carried on to the amidine 131. Upon either longer or more vigorous additional treatment (for example, higher temperatures) with a Lewis acid-ammonia reagent as described in Scheme 1b, the amide group can be converted to an aminoiminomethyl group to give a bisamidine compound 132.
Acid 13 can also be converted to an amine 47 from which sulfonamides, ureas and urethanes can be formed (Formula I where R2 or R3=NR32SO2R31, NHCONR51R52 or NHCOR31, respectively). Scheme 3a illustrates this methodology for introduction of these three groups at R2 of Formula I. Conversion of the acid 13 to an intermediate acyl azide can be followed by heating of such azide in the presence of an alcohol under Curtius rearrangement conditions to form the carbamate ester of the alcohol. Subsequent carbamate ester hydrolysis yields amine 47. The intermediate acyl azide may be synthesized by coupling the acid 13 to hydrazine through the acid chloride or by any of the amide coupling procedures discussed for Scheme 2e followed by nitrosation of the resulting hydrazide by any of the nitrosating agents discussed for conversion of 3 (R1=NH2) to 3 (R1=H) in Scheme 1c. More preferably conversion of 13 to 47 is carried out through treatment of acid 13 with diphenylphosphoryl azide in the presence of an alcohol, preferably tert-butanol, and a base, preferably triethylamine or DIEA, as shown in Scheme 3a, to give a tert-butylcarbamate that is readily decomposed to the salt of amine 47 on exposure to an acid, preferably HCl or trifluoroacetic acid in a suitable solvent such as CH2Cl2. Further treatment with a base such as NaOH or preferably K2CO3 or NaHCO3 provides the free base 47. Treatment of amine 47 with a sulfonyl chloride R31SO2Cl in the presence of an acid scavenger, such as pyridine or DIEA, followed by optional alkylation on nitrogen with an alkylating agent R32L in the presence of a base such as K2CO3, DIEA or more preferably sodium hydride, in a solvent such as THF, MeCN or CH2Cl2 affords the sulfonylamine functionality at R2 (48). When necessary, this transformation can be catalyzed by the presence of 4-dimethylaminopyridine for less reactive sulfonyl chlorides. Similar treatment of amine 47 with an isocyanate R51NCO or carbamyl chloride R51R52COCl affords the aminocarbonylamine functionality at R2 (50). Similar treatment of amine 47 with an acid chloride R31COCl affords the carbonylamine functionality at R2 (52). Conversion of the esters in 48, 50 and 52 to amidines as previously mentioned gives the products 49, 51 and 53. Further conversion of the acylamino group of 53 as discussed for synthesis of 132 also provides access to the iminomethylamino group at R2 (54).
Introduction of an aminosulfonyl group (including monoalkylaminosulfonyl and dialkylaminosulfonyl groups) for R2 of Formula I can be carried out starting from amine such as 47 as well. Conversion to a sulfonyl chloride by the method of Gengnagel, et al. (U.S. Pat. No. 3,947,512 (1976)) and treatment with an amine R34NH2 followed by optional alkylation on nitrogen with R35L (under the sulfonylation and alkylation conditions described in Scheme 3a) provides 56 which is further converted to amidines 57 as previously described.
In addition to the synthesis outlined in Scheme 3a, amine 47 may also be produced as illustrated in Scheme 3c. A nitrothienyl ester 122 (Dell""Erba, C. and Spinelli, D., Tetrahedron, 21: 1061 (1965), Dell""Erba, C. et al., J. Chem. Soc, Perkin Trans 2, 1779 (1989)) with a suitable leaving group L may be substituted with an anion of R21 to give intermediate 123. Amine 47 is then derived from reduction of the nitro group. Appropriate reagents to effect reduction of the nitro functionality include hydrogen gas in the presence of a catalyst such as palladium or platinum metal deposited on carbon or barium sulfate in any of a number of solvents such as methanol, ethanol, ethyl acetate, DMF or THF. More preferably, tin (II) chloride may be employed as a reductant in solvents such as DMF or THF, or in the presence of HCl in a solvent such as methanol or ethanol. Alternatively, metals such as zinc or iron (Stanetty, P. and Kremslehner, M., Heterocycles 48: 259 (1998)) may also be used.
Scheme 4a illustrates the preparation of the compounds of Formula III and Examples 48-59 and 61-77. The amidine moiety of compounds of structure 60 can be protected with a protecting group P1 that can be readily removed from 62 and 64 using methods known to those skilled in the art (Theodora W. Greene and Peter G. M. Wuts, John Wiley and Sons, Inc. 1991). For example, a tert-butoxycarbonyl (BOC) protecting group can be removed by exposure to strongly acidic medium such as hydrogen chloride in a suitable solvent such as dioxane, or by trifluoroacetic acid in a suitable solvent such as methylene chloride. Benzyloxycarbonyl (Cbz) protecting groups can be removed by catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran.
In some cases, P1 can be a solid support such as polystyrene or polyethyleneglycol-grafted polystyrene which can be attached to the amidine moiety via a cleavable linker such as 4-(benzyloxy)benzyloxy-carbonyl (using carbonate Wang resin). Attaching an amidine to a solid support can be achieved by treating a solid support having a linker containing an appropriately activated functional group with the amidine under suitable conditions. For example, an amidine can be attached to Wang resin by treating para-nitrophenylcarbonate Wang resin with the amidine and a suitable base such as DBU in a suitable solvent such as DMF. When D is OH or SH the protected amidines 61 can be alkylated with carboxy-protected (protecting group is R36) haloaliphatic acids, such as bromoacetic acid or bromopropionic acid in the presence of a suitable base such as cesium carbonate or DIEA, in a suitable solvent such as DMF with heating when necessary to give compounds of structure 62. When D is NO2, the nitro group can be reduced prior to alkylation using an appropriate reducing agent, such as tin (II) chloride, in a suitable solvent such as DMF, or by catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran. Other useful carboxy protecting groups are well known in the art (Theodora W. Greene and Peter G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley and Sons, Inc. 1991). For example, tert-butyl ester can be removed by exposure to strongly acidic medium such as hydrogen chloride in a suitable solvent such as dioxane, or such as trifluoroacetic acid in a suitable solvent such as methylene chloride. Benzyl ester can be removed by catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran or by base hydrolysis.
When protecting groups P1 and R36 in compounds 62 are orthogonal (as defined by the ability to remove one protecting group preferentially in the presence of the other), R36 can be preferentially removed to give acids 63. For example when P1 is BOC and R36 is OMe, the methyl ester can be removed by treating with a base such as sodium hydroxide in a suitable solvent such as aqueous tetrahydrofuran leaving the BOC group intact. When protecting groups P1 and R36 in compounds 62 are not orthogonal, both protecting groups are removed, and the amidine can be protected with a suitable protecting group such as BOC or a suitably functionalized resin. The protected amidine 63 can be treated with various amines under suitable amide coupling conditions, such as in the presence 1-hydroxy-7-azabenzotriazole (HOAt), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and DIEA to form amides of structure 64. The amidine protecting group can be then removed, for example by treating with an acid, such as trifluoroacetic acid in a suitable solvent such as methylene chloride, when a BOC protecting group is employed, to give amidines 65.
Scheme 4b illustrates a specific example which utilizes the method described in Scheme 4a. The amidine moiety of 66 can be monoprotected with a tert-butyloxycarbonyl group. The monoprotected phenoxyamidine 67 can be alkylated on the phenolic hydroxy group with an ester of 2-bromoacetic acid to give 68. In the case where the ester can be removed by base, it can be hydrolyzed with aqueous base, such as NaOH, to give the acid 69. This acid can be treated with various amines in the presence of 1-hydroxy-7-azabenzotriazole (HOAt), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and DIEA to form amides of structure 70. The amines are unsubstituted, di- or mono-substituted aliphatic or aromatic amines. In some cases the amines are cyclic-amines such as piperazine and piperidine. The amides 70 are then treated with trifluoroacetic acid to give the amidines 71. In the case where the ester 68 is acid-labile, it can be treated with trifluoroacetic acid to give the amidino-acid 72. This amidine can be loaded on to an insoluble support, such as polystyrene or polyethyleneglycol-grafted polystyrene via a cleavable linker, such as Wang, which is functionalized as an activated carbonate such as p-nitrophenylcarbonate or succinimidyl carbonate. Generally this can be done by treating the activated carbonate resin with the amidine and a suitable base such as DBU in a suitable solvent such as DMF. The support-bound acid 73 can be treated with various amines in the presence of 1-hydroxy-7-azabenzotriazole (HOAt), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and DIEA to form amides. These amides are then cleaved from the solid support by treating with trifluoroacetic acid to give compounds of structure 71.
Scheme 5 illustrates a synthetic route to amidines containing di-substituted thiazoles represented by compounds for which R2 is Formula II and both R8 and R9 are non-hydrogen substituents. The ketoamide 74 can be converted to the mono-bromoketoamide by treating with bromine in acetic acid. Thiazoles 76 are formed by reacting the bromoketoamide with 10 under suitable conditions, preferably by heating the mixture in DMF or acetone. Amidines 77 are formed by heating 76 in toluene with trimethylaluminum and ammonium chloride. The amidines 77 are treated with strong acid such as HCl to give the acids 78. The amidines 78 are in one route protected with a suitable protecting group such as BOC to give 79. The protected amidines 79 are treated with various amines under suitable coupling conditions, such as in the presence of HOAt, HATU, and DIEA to form various amides. The amidine protecting group can be then removed, for example by treating with trifluoroacetic acid in a suitable solvent such as methylene chloride, when a BOC protecting group is employed to give amidines 80. In a second route, the amidines 78 can be loaded onto an insoluble support, such as polystyrene or polyethyleneglycol-grafted polystyrene via a cleaveable linker, such as Wang resin, which is functionalized as an activated carbonate ester, such as p-nitrophenylcarbonate or succinimidyl carbonate, to give a resin-bound scaffold 81. The resin-bound acid 81 can be treated with various amines under suitable coupling conditions such as in the presence of HOAT, HATU and DIEA to form amides. These amides are then cleaved from the solid support by treating with trifluoroacetic acid to give amidines 80.
Scheme 6a illustrates the preparation of compounds of Examples 144, 145, 146, 147, 148, 149, 150 and 151. Compounds of this invention correspond to those of Formula I where R2 is Formula II and where Ar is thiazole and R37 and R38 (R8 and R9 of Formula II) are phenyl, which can be additionally substituted. Starting from 2,5-dibromothiophene 90, treatment with lithium diisopropylamide followed by R21L, where L is a leaving group, preferably a halogen, mesylate, tosylate, or methyl sulfate, and more preferably iodomethane or methyl sulfate, according to the procedure of Kano, et al., Heterocycles 20(10):2035 (1983), gives 91. Compound 91 can be treated with an appropriate base, preferably a lithium alkyl like n-butyllithium, sec-butyllithium, or t-butyllithium, and more preferably n-butyllithium, followed by carbon dioxide gas and conversion of the resulting carboxylate salt to the free acid with a mineral acid, preferably hydrochloric acid. Conversion to ester 21 can be carried out by preparation of the acid chloride using oxalyl chloride and treatment of this intermediate acid chloride with an alcohol R23 in an appropriate solvent, preferably dichloromethane, with an appropriate base, preferably pyridine. Compound 21 can be treated with copper (I) cyanide in refluxing dimethylformamide to give compound 9. Compound 9 can be treated with hydrogen sulfide gas in an appropriate solvent, preferably methanol, containing an appropriate base, preferably triethylamine to give compound 10. Compound 10 can be treated with an appropriate ketone where L is a leaving group, preferably halogen, mesyl, or tosyl, and most preferably bromo, refluxing in a suitable solvent, preferably, acetone, dimethylformamide, dimethyl acetamide, methyl ethyl ketone, or other polar aprotic solvents, and most preferably acetone to give compound 92. Compound 92 is treated with an appropriate reagent, preferably the aluminum amide reagent to give amidine 93.
Scheme 6b illustrates the preparation of the compound of Example 144, which corresponds to a compound for which R2 is Formula II, and where Ar is thiazole and R8 and R9 (R37 and R38 in Scheme 6b) are phenyl, which can be optionally substituted. Starting from 2,5-dibromothiophene 90, treatment with n-butyllithium produces an anion which undergoes a rearrangement (Kano, S., et al, Heterocycles 20:2035 (1983)). Quenching with carbon dioxide gas and conversion of the resulting carboxylate salt to the free acid with a mineral acid, preferably hydrochloric acid, gives acid 94. Conversion to ester 95 can be carried out by preparation of the acid chloride using oxalyl chloride and treatment of this intermediate acid chloride with an alcohol R23xe2x80x94OH in an appropriate solvent, preferably dichloromethane, with an appropriate base, preferably pyridine. Compound 95 can be treated with copper (1) cyanide in refluxing dimethylformamide to give compound 96. Compound 96 can be treated with hydrogen sulfide gas in an appropriate solvent, preferably methanol, containing an appropriate base, preferably triethylamine to give compound 97. Compound 97 can be treated with an appropriate ketone where L is a leaving group, preferably halogen, mesyl, or tosyl, and most preferably bromo, refluxing in a suitable solvent, preferably, acetone, dimethylformamide, dimethyl acetamide, methyl ethyl ketone, or other polar aprotic solvents, and most preferably acetone to give compound 98. Compound 98 is treated with an appropriate reagent, preferably the aluminum amide reagent (Al(CH3)3/NH4Cl) to give amidine 99.
Scheme 7a illustrates the preparation of compounds for which R2 is Formula II and Ar is thiazol-4-yl. As illustrated, the acids 13 can be converted to their acid chlorides by treatment with oxalyl chloride with dimethylformamide catalysis in methylene chloride, or by using thionyl chloride, either neat or in an organic solvent, at ambient or elevated temperature. Compounds are then homologated to the desired a-haloketones 100 by sequential treatment with trimethylsilyldiazomethane and hydrogen bromide. An alternative would be to substitute diazomethane (generated from Diazald(copyright), Aldrich Chemical Co., Milwaukee, Wis.) for the trimethylsilyldiazomethane. Also, the conversion of 13 to 100 can be effected using the procedure derived for the synthesis of compound 42 from compound 46.
The alpha-haloketones 100 are then allowed to react with the appropriate thiourea (Scheme 7b) or thioamide derivative in an organic solvent, preferably acetone or dimethylformamide at 70xc2x0 C. to give 2-aminothiazoles or thiazoles 101.
The thiazoles 101 can be treated with the aluminum amine reagent (Al(CH3)3/NH4Cl) formed at ambient temperature by the reaction of trimethylaluminum with ammonium chloride in an organic solvent, preferably toluene. The ester can then be converted to the amidines 102 at elevated temperatures, preferably higher than 80xc2x0 C.
As shown in Scheme 7b, amines 110 (or their hydrochloride salts) can be converted to their respective mono-substituted thioureas (methan-1-thiones) 112 by treatment with thiophosgene to form the intermediate isothiocyanates 111. Preferred conditions include treating the amine with thiophosgene in a biphasic solvent system composed of a halogenated solvent such as chloroform and an aqueous phase of saturated sodium bicarbonate. Alternatively, the reaction may be effected by treatment of 110 with a hindered amine and thiophosgene such as triethylamine or diisopropylethylamine in an organic solvent such as tetrahydrofuran or methylene chloride. Another alternative to forming isothiocyanates 111 is the direct treatment of primary amines and carbon disulfide in pyridine with dicyclohexylcarbodiimide (Jochims, Chem. Ber. 101:1746 (1968)).
Isothiocyanates 111 can be converted to thioureas 112 by treatment with an ammonia-alcohol solution, preferably a 2M ammonia in methanol or ethanol solution, at room temperature or elevated temperatures ( greater than 70xc2x0 C.). Alternatively, the thioureas 112 can be prepared directly form the appropriate urea (or thioamide from the appropriate amide when R8=alkyl or aryl)) by treatment with Lawesson""s reagent (Lawesson, S.-O., et. al. Bull. Soc. Chim. Belg. 87:223, 293 (1978)).
Scheme 8 illustrates the preparation of compounds of this invention where R2 is Formula II and Ar is thiazole and R37 and R38 are phenyl which is further substituted by a sulfonylamino or carbonylamino group. Starting from thioamide 10, treatment with a nitro substituted 2-halo-acetophenone, where the halogen is chloro, bromo, or iodo, preferably bromo, refluxing in a suitable solvent, preferably acetone, dimethylformamide, dimethyl acetamide, methyl ethyl ketone, or other polar aprotic solvents, and most preferably acetone. The reduction of nitroaryl compound 113 can be carried out with a suitable reducing agent, preferably tin (II) chloride, titanium (II) chloride, iron (III) chloride, lithium metal, sodium metal, catalytic hydrogenation over platinum or palladium catalyst, and most preferably 20% aqueous solution of titanium (III) chloride. The acylation of aniline 114 can be carried out with an appropriate acyl compound R42L where L is a halogen, preferably chloro, in an appropriate solvent, preferably dichloromethane, containing a base, preferably pyridine, N-methylmorpholine, or diisopropylethylamine. Alternatively, the acylation of aniline 114 is carried out with an activated carboxylic acid compound R42COL where L is hydroxy activated with dicyclohexylcarbodiimide, ethyl-3-(diethylamino)propylcarbodiimide (EDAC), O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (HATU), or pentafluorophenyl. The sulfonylation of aniline 114 can be carried out with and appropriate sulfonyl chloride compound R41SO2L in an appropriate solvent, preferably dichloromethane, containing a base, preferably N-methyl morpholine, diisopropylethylamine, or pyridine, most preferably N-methyl morpholine, with or without a condensation catalyst, preferable dimethylaminopyridine (DMAP). The amidinylation of compounds 115 and 117 can be carried out with an appropriate reagent, preferably the aluminum amide reagent (Al(CH3)3/NH4Cl)
Scheme 9 illustrates the preparation of compounds of Formula I, for which one of R5 and R6 is a non-hydrogen substituent. The amidines 5 are converted to the amidoximes 119 by heating with hydroxylamine in a suitable solvent such as ethanol. The cyanoamidines 120 are prepared by heating the amidines 5 with cyanamide in a suitable solvent such as ethanol. (Huffman, K. R. and Schaeffer, F., J. Amer. Chem. Soc. 28:1812 (1963). Alternatively 5 can be heated with an amine such as methylamine to give the N-alkylated amidines 121.
Scheme 10 illustrates an approach to compounds of Formula I where X=S or O, R2=arylamino, R3=alkylthio, aralkylthio, arylthio, alkyloxy, aralkyloxy, aryloxy, alkylamino, dialkylamino, aralkylamino, diaralkylamino, arylamino or diarylamino, Y=bond and Z=NR5R6.
Aminothiophenes 47 (Formula I where X=S, or O; R2=NH2) can be reacted with an arylboronic acid (R56B(OR58)2, R58=H) or arylboronic ester (R56B(OR58)2, R58=alkyl) in the presence of a copper catalyst, preferably copper (II) acetate, and an amine base such as triethylamine or pyridine (Chan, D. M. T. et al., Tetrahedron Lett 39: 2933 (1998)) to give a thienylarylamine 124. Conversion of the ester to amidine 125 is carried out in the manner previously described in Scheme 1b.
Another route to compounds of this invention, where R2=arylamino or alkylarylamino and alkylamino and where R3, Y and Z are as described in Scheme 10, is shown in Scheme 11 where intermediate 2 (R21=R3, L=leaving group) is aminated using conditions well known in the art. (See for example: Ahman, J. and Buchwald, S. L., Tetrahedron Lett. 38: 6363 (1997) and Wolfe, J. P. and Buchwald, S. L., Tetrahedron Lett. 38: 6359 (1997). For reviews see: Frost, C. G and Mendonca, P., J. Chem. Soc, Perkin Trans 1: 2615 (1998) and Wolfe, J. P. et al., Acc. Chem. Res. 31: 805 (1998).) Thus, 2 may be treated with an aniline R56R57NH (R56=aryl, R57=H or alkyl) in the presence of a palladium catalyst, a suitable palladium ligand and a base to give 127. Suitable catalysts include any of a number of Pd(0) or Pd(II) salts, such as tetrakis(triphenylphosphino) palladium (0), dichlorobis(acetonitrile)palladium (II) or preferably palladium (II) acetate or tris(dibenzylideneacetone)dipalladium. The most appropriate ligands for any given reaction are often compound-dependent and are discussed in detail in the aforementioned references but may include 1,1xe2x80x2-bis(diphenylphosphino)ferrocene (DPPF), 1-[2-(diphenylphosphino)ferrocenyl]ethyl methyl ether (PPF-OMe), or preferably 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl (BINAP). Appropriate bases include sodium t-butoxide or preferably cesium carbonate or potassium phoshate. Useful solvents include DMF, dioxane, dimethoxyethane or preferably toluene. Conversion of the ester to amidine 128 is carried out in the manner previously described in Scheme 1b.
The corresponding compounds of Formula I where R2=alkylamino and R3, Y and Z are as described in Scheme 10 are produced as shown in Scheme 12 by initial reductive alkylation of amine 47 with an aldehyde R59CHO or ketone R59COR60 in the presence of any of a number of suitable reducing agents including sodium borohydride, sodium cyanoborohydride or, more preferably, sodium or tetraalkylammonium salts of triacetoxyborohydride to give 129. Depending on the reducing agent employed, suitable solvents may include an alcohol, such as methanol, ethanol or isopropanol, or solvents such as THF or dichloromethane. Conversion of the ester to the amidine 130 is again carried out in the manner previously described in Scheme 1b.
Scheme 13 illustrates an approach to compounds of Formula I where R2 is a 2-thiazolylamino and R3, Y and Z are as described in Scheme 10. In this method, amine 47 can be first converted to a thiourea 131 using the various procedures outlined in Scheme 7b. Further reaction of the thiourea with a leaving group-substituted ketone R37COCH(L)R38, preferably a 2-haloketone as described in Schemes 2f, 2g or 2h, can provide thiazolylaminothiophenes 132 which are then converted to the corresponding amidines 133 by the previously described methodology of Scheme 1b. 